Therapeutic drug combinations against COVID-19 obtained by employing a collaborative filtering method

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) has severely harmed human society and health. Because there is currently no specific drug for the treatment and prevention of COVID-19, we used a collaborative filtering algorithm to predict which traditional Chinese medicines (TCMs) would be effective in combination for the prevention and treatment of COVID-19. First, we performed drug screening based on the receptor structure prediction method, molecular docking using q-vina to measure the binding ability of TCMs, TCM formulas, and neo-coronavirus proteins, and then performed synergistic filtering based on Laplace matrix calculations to predict potentially effective TCM formulas. Combining the results of molecular docking and synergistic filtering, the new recommended formulas were analyzed by reviewing data platforms or tools such as PubMed, Herbnet, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, the Guide to the Dispensing of Medicines for Clinical Evidence, and the Dictionary of Chinese Medicine Formulas, as well as medical experts' treatment consensus in terms of herbal efficacy, modern pharmacological studies, and clinical identification and typing of COVID-19 pneumonia, to determine the recommended solutions. We found that the therapeutic effect of a combination of six TCM formulas on the COVID-19 virus is the result of the overall effect of the formula rather than that of specific components of the formula. Based on this, we recommend a formula similar to that of Jinhua Qinggan Granules for the treatment of COVID-19 pneumonia. This study may provide new ideas and new methods for future clinical research.

Classification

Biological Science.

1. Introduction

The novel coronavirus pneumonia (coronavirus disease 2019, COVID-19) is an emerging acute respiratory infectious disease. The pathogen is a β genus coronavirus, and the disease is mainly spread by respiratory droplets and close contact transmission, which can lead to severe respiratory infectious diseases.1 Novel coronavirus (2019-nCoV) is a single-stranded positive-stranded RNA virus that is widely spread from human to human and causes severe infections. It encodes four structural proteins (S, E, M, and N), 16 non-structural proteins (helicase, protease, RNA polymerase, and others), and eight helper proteins. All proteins of the new coronavirus work together to complete the process of viral infection of the body, as well as replication and translation.

COVID-19 has the ability to strongly infect due to a Flynn protease cleavage site in COVID-19's S protein, which exposes a C-terminal regular peptide that can bind to the NRP1 protein after being cleaved by Flynn protease, which promotes novel coronavirus's endocytosis into the alveoli after binding to NRP1 protein. However, SARS has no cleavage site for Flynn protease and can only be mediated by ACE2 on the alveoli surface [1]. Regarding a variant of concern (VOC), as put forward by the World Health Organization (WHO), there have been five, which are Alpha, Beta, Gamma, Delta, and Omicron. Pre-Omicron infection cases have currently replaced the Delta strain as the main epidemic strain.2 According to the data released by Johns Hopkins University,3 as of April 28, 2022, the number of people infected with COVID-19 worldwide reached 52,255,815, and the death toll was 6,228,402. According to relevant statistics, the economic losses of countries around the world have exceeded 9 trillion US dollars due to the continuous impact of the pandemic.

Since the outbreak of the COVID-19 epidemic, there has been no specific drug for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Traditional drug development strategies are not feasible to produce new drugs for COVID-19 because of the time-consuming nature of drug discovery, as well as high costs and high failure rates. Therefore, there is a need to find treatments that can be immediately applied to reduce mortality and morbidity. Vaccine development typically occurs over a period of 12–18 months, and the time required to approve a new antiviral treatment may exceed 10 years.

To counter the rapid spread of COVID-19 in the absence of a specific drug, drug repurposing can greatly accelerate the implementation of new treatments [2]. Although it has always been challenging to derive a monotherapeutic agent with anti-novel coronavirus activity, promising alternatives can be developed utilizing collaborative drug combinations. A synergistic combination can increase treatment efficacy or achieve a stronger therapeutic effect and/or result with a concomitant reduction of the required dose, thereby reducing side effects. Drug repositioning is a quick and effective method to provide this kind of treatment.

Despite the development of vaccines, scientists tirelessly continue to design new drugs and repurpose existing drugs against SARS-CoV-2. Although tremendous strides have been made in the fight against coronaviruses, a lack of safe and effective anti-SARS-CoV-2 drugs is still a key factor restricting the prevention and control of COVID-19 pandemics [3]. Pfizer has recently launched a new specific anti-novel coronavirus drug (brand name Paxlovid) consisting of co-packaged 150 mg nirmatrelvir tablets and 100 mg ritonavir tablets. The core antiviral component, nirmatrelvir, works by inhibiting the main protease (M pro) of SARS-CoV-2, also known as 3C protease (3CLpro) or nsp5 protease [4]. However, recent studies have shown that Paxlovid causes serious side effects, such as impaired taste, diarrhea, high blood pressure, and muscle soreness. Additionally, simultaneous use of Paxlovid with some other drugs may lead to potentially significant drug interactions [5].

Previous studies have shown that a variety of western drugs may block neo-coronavirus infection, but thus far, there are still no specific efficacious drugs. Prof. Boli Zhang of Tianjin University of Traditional Chinese Medicine has proposed six TCM formulas (Qingfei Paidu Decoction, Xuanfei Baidu Formula, Huashi Baidu Formula, Jinhua Qinggan Granules, Lianhua Qingwen Capsules, and Xuebijing Injection) to treat COVID-19. Jinhua Qinggan Granules, e.g., are extracted from Yinqiao Powder and Maxing Shigan decoction, and the substance is further refined by the subsequent removal and addition of some Chinese herbal medicines from the formula. This herbal product is well-known for dispelling wind, invigorating the lungs, clearing heat, and detoxification [6].

Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-Although the novel coronavirus continues to mutate, the vaccine is still effective in preventing severe illness and death [7]. At the present stage, most infected people are asymptomatic and mild. Jinhua Qinggan Granules is effective and more accurate at this stage.In addition, on March 31, 2020, the State Medical Products Administration converted Jinhua Qinggan Granules from a prescription drug to A Class A non-prescription drug, which fully demonstrated its clinical applicability and practicability.4 Current studies have fully verified the clinical effectiveness, antiviral activity, and anti-inflammatory effect of Jinhua Qinggan Granules. Network pharmacological studies indicate that Jinhua Qinggan granules contain a variety of active components, such as formononetin, stigmasterol, β-quebrholin, and icariin. By combining this formula with 3C-like proteolytic enzyme (3CLPro) and angiotensin-converting enzyme 2, it can regulate PTGS2, HSP90AB1, HSP90AA1, PTGS1, and other pathways, thus controlling SARS-CoV-2. These proposed mechanisms could explain the shortened recovery time of COVID-19 symptoms secondary to the host inflammatory response after infection [8]. Jinhua Qinggan granule, the other traditional Chinese patent medicine (CPM), is composed of Forsythia suspensa (Thunb.) Vahl, Lonicera japonica Thunb., Ephedra sinica Stapf., Prunus armeniaca L., l-menthol, Glycyrrhiza glabra L., Scutellaria baicalensis Georgi, Fritillaria thunbergia Miq., Anemarrhena asphodeloides Bunge, Arctium lappa L., and Artemisia annua L., and has been approved to treat H1N1 influenza virus infection since 2009. In March 2020, the State Medical Products Administration announced that Jinhua Qinggan Granules will be converted from prescription drugs to Class A non-prescription drugs. The State Food and Drug Administration issued supplementary approval in May 2020, Jinhua Qinggan granule is suitable for the treatment of mild and common types of novel coronavirus pneumonia. Recently, the experts conducted a phase 2/3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of JHQG in patients with mild, non-hospitalized, laboratory-confirmed COVID-19. The JHQG group showed greater clinical efficacy (82.67%) on the 10th day of treatment in contrast with the placebo (10.74%). The recovery time for the JHQG group from cough, sputum, sore throat, dyspnea, headache, nasal obstruction, fatigue, and myalgia symptoms was shorter as compared to the placebo group (6 vs. >11 days; P < 0.05). In the latest RCT, JHQG combined with western medicine relieved the clinical symptoms of fever and poor appetite in patients with COVID-19 and reduced the use of antibiotics to a certain extent. Based on the time to recover from the COVID-19-related symptoms and AEs, it is concluded that JHQG is a safe and effective TCM for symptomatic relief of patients with mild COVID-19. A symptomatic improvement in the JHQG group patients was observed and JHQG use would have important public health implications in such patients [9]. Jinhua Qinggan granule have been widely used based on the diagnosis according to TCM theory, and they show superiority over general treatments. This reflects the advantages of using TCM to treat COVID-19. TCM is helpful not only for patients with different symptoms but also for those at different stages of the disease. It is recommended to halt or slow the progression of COVID-19 during either the observation period or when symptoms manifest [10,11]. An official report has shown that 91.5% of patients with COVID-19 have used TCM therapies in China, and the efficacy is greater than 90%.5

Holism forms the crucial foundation on which the theory of TCM is based, which emphasizes the connection of the whole body and aims to treat the whole person, rather than focusing on treating the individual symptoms. Following the guidance of holistic theory, TCM adopts syndrome differentiation and treatment, comprehensively analyzes all types of clinical information, and uses TCM prescriptions for the treatment of patients' single or complex discomfort. Western medicine therapy has a clear definition of the chemical properties and pharmacological effects of individual compounds, while the formulation of Chinese herbal medicine is based on the theory of TCM (“Peiwu” and “Jun-Chen-Zuo-Shi” in Chinese) [12]. It is believed that the complex synergistic interactions among the herbs in complex Chinese herbal medicine formulations (Fufang in Chinese) are able to enhance the bioavailability of active components, promote therapeutic effects, and/or reduce toxicity.

The design of herbal formulations follows the principle of compatibility, called combination of medicinals, which requires the consideration of different interrelationships of herbal ingredients, including synergism (Xiang Xu in Chinese), assistance (Xiang Shi in Chinese), detoxication (Xiang Sha and Xiang Wei in Chinese), antagonism (Xiang Wu in Chinese), and rejection (Xiang Fan in Chinese) [13]. Based on this principle, different herbs are combined following the monarch–minister–assistant–courier (Jun–Chen–Zuo–Shi in Chinese) rule to achieve desirable effects and/or to minimize side effects. Jun is the main herb in an herbal formula with a relatively higher ratio to directly target the disease; Chen is an adjuvant herb to promote the therapeutic effect of the key herb or to target the accompanying symptoms; Zuo is usually used for reducing the side effects of the herbal formula, and Shi is the herb that guides the active ingredients to reach the target organs or to harmonize their actions.

It is important not to confuse synergistic effect with additive effect. Synergy occurs when two or more drugs/compounds are combined to produce a total effect that is greater than the sum of the individual agents, while an additive effect is the sum of individual effects, where each agent is not affecting the other (no interactions) [14,15]. The concept that the additive effect of two drugs is their arithmetic sum is a misconception. The additive effect is not simply the sum of the effects of A plus B. Significant challenges remain in the development of suitable methods for synergistic studies of complex herbal combinations [12].

Historically, the Chinese people have employed TCM in response to epidemics along with the development of Chinese civilization. Chinese medicine has developed theories and effective prescriptions for the prevention and treatment of epidemics, which have been recorded in many classic TCM books, such as the Treatise on Acute Epidemic Febrile Diseases, the earliest existing and well-known treatise on the treatment of acute infectious diseases written by Youxing Wu in 1642 [16]. TCM diagnosis and treatment theory were used in response to several destructive epidemics, including smallpox, malaria, and leprosy, and prevented further transmission. Smallpox vaccination was invented in the Song dynasty in China through smallpox scabs. TCM also played an important role during the fight against SARS in 2003 and resulted in the lowest mortality rate in mainland China [17,18]. April 25, 2022 was World Malaria Day and the 50th anniversary of the advent of artemisinin. Half a century later, artemisinin remains an important antimalarial drug in the world because it has saved millions of lives around the world and greatly contributed to the global cause of malaria. It is a gift of TCM to the world. President Azaly of Comoros spoke highly of artemisinin when he recently acknowledged the 50th anniversary of artemisinin and the international forum with the goal of building a community of human health.6

In 2015, Youyou Tu won the Nobel Prize in Physiology or Medicine for her discovery of artemisinin. Youyou Tu and her colleagues discovered and developed artemisinin and its derivatives, which are the fastest effective drugs against falciparum malaria. They are the first specific antimalarial drugs where scientific methods were used to develop them from traditional medicines. From the treatment of SARS to the fight against malaria to COVID-19 today, TCM incorporates ideas that are different from the microbiology-oriented knowledge of disease etiology or the mechanism of novel drugs, and it emphasizes the relief of symptoms to cure infected patients and control the spread of epidemics [19]. On March 31, 2022, the World Health Organization (WHO) released the “World Health Organization Expert Evaluation Meeting on Traditional Chinese Medicine against COVID-19” on its official website, which fully affirmed the contribution of TCM in fighting the epidemic situation of COVID-19. The report notes that TCM can effectively treat COVID-19, decrease the conversion of mild cases to severe cases, shorten the virus clearance time, and improve the clinical prognosis of mild and common COVID-19 patients.7

In the long history of fighting against epidemics, TCM has formed a complete theoretical and practical system regarding the etiology, pathogenesis, and treatment principles for epidemic diseases. During the COVID-19 epidemic, there were unique advantages to using TCM for treatment. Based on the above research, we can conduct computer simulations through structure-based drug design to investigate the mechanism of action of the six formulas and make new recommendations for the synergistic combination of other TCM drugs in combination with the recommended six formulas to provide new ideas and new methods for the treatment of COVID-19 with TCM.

2. Materials

To explore the mechanism of action of TCM on novel coronavirus, we selected the ingredients of six TCM formulas, docked with novel coronavirus's 24 middle protein, and integrated the docking results into drugs and formulas. First, the data for the TCM compounds were downloaded from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database.8 The TCMSP database includes the characteristics of the compounds contained in TCMs. A total of 482 TCMs and 13448 compounds were downloaded. Second, we downloaded the COVID-19 protein data from the Research Collaboratory for Structural Bioinformatics (RCSB),9 including 24 structural COVID-19 proteins and COVID-19 proteins based on template prediction, and then docked the compounds and proteins. Then, we reviewed the drug-compound matrix according to absorption, distribution, metabolism, and excretion (ADME)10 and isolated agents based on efficacy, properties, menstruation, and other information regarding the above drugs from the Herbnet11 database of the Institute of TCM Information of the Chinese Academy of TCM. Finally, we standardized the agents to obtain a similarity matrix and calculate the similarity.

3. Methods

We cannot know whether the therapeutic effect is due to the main drugs in the prescription, the main components of the main drugs, or the overall effect of the prescription, and therefore, we carried out the molecular docking between the drug compounds in the six formulas and novel coronavirus to explore the mechanism of drug action in COVID-19 infection.

We first measured the binding ability of TCMs, TCM formulas, and novel coronavirus proteins based on q-vina molecular docking, and then created a TCM formula using a collaborative filtering algorithm based on Jinhua Qinggan granules.

3.1. Molecular docking

The score and spatial conformation were analyzed using molecular docking synthesis. The scoring function, i.e., the binding capacity between ligand and receptor molecules, was derived by a comprehensive assessment using a more efficient algorithm, which is generally evaluated using energy matching.

The derivation of the scoring function combines certain advantages of the knowledge potential and the empirical scoring function (Eqs (1), (2), (3)). It extracts empirical information from conformational preferences and experimental affinity measurements of receptor-ligand complexes. The scoring function, i.e., the calculation of the binding free energy, is explained differently in different articles, and in this work, the scoring function c is calculated using the following equation [20]:

$$\begin{array}{c}c={\mathrm{\Sigma }}_{\left(i<j\right)}{f}_{\left(t_i{t}_j\right)}\left(r_{ij}\right)\text{.}\end{array}$$ (1)

Each atom i is assigned a type that should define the inter-atomic distance ${\mathrm{r}}_{\mathrm{i}\mathrm{j}}$ of the symmetric interaction function ${\mathrm{f}}_{{\mathrm{t}}_{\mathrm{i}}{\mathrm{t}}_{\mathrm{j}}}$.

$$\begin{array}{c}{\mathrm{f}}_{{\mathrm{t}}_{\mathrm{i}}{\mathrm{t}}_{\mathrm{j}}}\left({\mathrm{r}}_{\mathrm{i}\mathrm{j}}\right)\equiv {\mathrm{h}}_{{\mathrm{t}}_{\mathrm{i}}{\mathrm{t}}_{\mathrm{j}}}\left({\mathrm{d}}_{\mathrm{i}\mathrm{j}}\right),{\mathrm{d}}_{\mathrm{i}\mathrm{j}}\equiv {\mathrm{r}}_{\mathrm{i}\mathrm{j}}-{\mathrm{R}}_{{\mathrm{t}}_{\mathrm{i}}}-{\mathrm{R}}_{{\mathrm{t}}_{\mathrm{j}}}\text{,}\end{array}$$ (2)

where ${\mathrm{R}}_{\mathrm{t}}$ denotes the van der Waals radius of a t-type atom.

In Eq. (2), the ${\mathrm{h}}_{{\mathrm{t}}_{\mathrm{i}}{\mathrm{t}}_{\mathrm{j}}}$ is a weighted sum of spatial interactions, including all pairs of atoms with different weights, hydrophobic interactions between hydrophobic atoms, and hydrogen bonding forces.

$$\mathrm{G}\mathrm{a}\mathrm{u}\mathrm{s}{\mathrm{s}}_1\left(d\right)=e^{-{\left(d/0.5\AA \right)}^2}\text{,}$$

$$\mathrm{G}\mathrm{a}\mathrm{u}\mathrm{s}{\mathrm{s}}_2\left(d\right)=e^{-{\left((d-3\AA /2\AA \right)}^2}\text{,}$$

$$Repulsion\left(d\right)=\{\begin{array}{c}{d}^2,d<0\\ 0,d\ge 0\end{array}\text{,}$$

$$Hydrophobic\left(d\right)=\{\begin{array}{c}1,d<0.5\AA \\ 1.5\AA -d,0.5\AA \le d\le 1.5\AA ,\\ 0,d>1.5\AA \end{array}$$

$$Hydrogenbonding\left(d\right)=\{\begin{array}{c}1,d<-0.7\AA \\ \frac{d}{0.7\AA },-0.7\AA \le d\le 0\\ 0,d>0\end{array}\text{,}$$

$$\begin{array}{c}{f}_{t_i{t}_j}=\{\begin{array}{c}{\mathit{w}}_{\mathbf{1}}*\mathrm{G}\mathrm{a}\mathrm{u}\mathrm{s}{\mathrm{s}}_1\left(\mathit{d}\right)+{\mathit{w}}_{\mathbf{2}}*Gaus{s}_2\left(\mathit{d}\right)+{\mathit{w}}_{\mathbf{3}}*Repulsion\left(\mathit{d}\right)+\\ {\mathit{w}}_{\mathbf{4}}*Hydrophobic\left(\mathit{d}\right)+\\ {\mathit{w}}_{\mathbf{5}}*Hydrogenbonding\left(\mathit{d}\right)\end{array}\text{.}\end{array}$$ (3)

The drug compound protein binding affinity (scoring function) was calculated using this function in Eq. (3).

The entire range of proteins was directly framed for docking for small and larger structures. The proteins were divided into multiple regions and docked separately, and then, the results were manually combined. The docking results were analyzed using a scoring function combined with free energy. From a thermodynamic point of view, the ligand-receptor interaction is an integrated equilibrium process, and the stable conformation of a biomolecule is the conformation with the lowest free energy. Therefore, we used the binding affinity (binding free energy) to determine the binding of the protein to the drug compound (Eq. (3)). When the binding free energy was less than −7 kcal/mol, we determined that the compound was able to effectively bind to the protein and vice versa. Compound and protein were docked 10 times, and the average was taken as the docking result and used to construct the compound protein matrix.

3.2. Matrix construction rules

Based on ADME, compound free energy docking thresholds, drug compound dichotomous matrixes, and compound protein matrixes were generated.

3.3. Collaborative filtering

3.3.1. Molecular fingerprint calculation

We obtained the recommended drug combinations by a collaborative filtering algorithm, adding the structural information of the compounds themselves as auxiliary information for collaborative filtering on top of the docking values. The structural features of the compounds were extracted by molecular fingerprinting, and we chose two methods, MACCS, and RDK, to extract the molecular fingerprints, where the MACCS algorithm generated a vector of length 167. A total of 166 substructures were assigned a value of 1 if they had substructures, and 0 otherwise. The RDK algorithm checks the subgraphs between min path to max path and performs hashing operations on the subgraphs considering the 3 features of atomic type, aromaticity, and bond type. The length of its generated molecular fingerprint defaults to 2048. The molecular fingerprints of the compounds contained in the TCM are accumulated as the molecular fingerprints of the TCM.

3.3.2. Molecular fingerprint calculation

The information regarding the efficacy, medicinal properties, and attribution of the above drugs was obtained from the Herbnet database of the Institute of Chinese Medicine Information, Chinese Academy of TCM. The above information was normalized and later transformed into vectors of a specific length. The vector length was 739 dimensions, of which the medicinal properties were 40 dimensions in total, mainly including cold and heat, toxicity, and five flavors. There were 14 total dimensions for the attributive meridian and 685 total dimensions for efficacy, which was assigned as 1 if the drug contained word features, and 0 otherwise.

3.3.3. Similarity calculation

The similarity between drugs was calculated by molecular fingerprints and efficacy traits of TCMs. The molecular fingerprint vectors of TCM obtained by summation were transformed into one-hot vectors and spliced with the efficacy trait vectors obtained in 2, followed by the Tanimoto similarity calculation to obtain a total TCM-TCM similarity matrix.

3.3.4. Calculation of similarity between TCMs and formulas

The similarity between the 482 drugs and the three drugs tripartite was calculated, and the similarity between the drug and each herbal medicine in the formula (i.e., the corresponding value in the drug-drug similarity matrix) was calculated separately and weighted according to the position of the drug ruler and minister contained in the formula. The similarity values between Chinese medicine and the formula were obtained.

3.3.5. Calculation of similarity of TCM-Jinhua Qinggan Granules

The similarities between the 482 drugs and the 12 drugs in the 12 flavors in Jinhua Qinggan granules were calculated separately, and the top 20 drugs with the highest drug similarity were formed into a $12\times 20$ matrix of similar drugs. The proportion of drugs in this matrix included in the guideline-recommended Chinese herbal medicines was calculated.

4. Results

4.1. Docking results for the compounds in the six formulas

When the results of compound drug docking for the six formulas were not screened by ADME, the mean of 24 protein-free energy values was obtained, and 548 compounds were below −7, with the lowest result of −10.21 for neo-przewaquinone a. At the same time, the lowest free energy values of seven proteins (E, NSP4, NSP7, NSP8, ORF7A, ORF8, and ORF10) were obtained. The lowest free energy value was present in Chinese salvia root (Salvia miltiorrhiza Bunge; Dan Shen), followed by xambioona in licorice (Glycyrrhiza glabra; Gan Cao) with a free energy mean of −8.89. ADME was used to identify 90 compounds below −7, among which the lowest free energy value was for xambioona. It was followed by 6-(3-oxoindolin-2-ylidene) indole [2,1-b] quinazoline-12-one with a free energy mean value of −8.51 that was present in American ginseng (Panax quinquefolium; Ban Lan Gen), Dyer's woad leaf (Isatis tinctoria L.; Da Qing Ye), and natural indigo (Polygonum tinctorium Aiton; Qing Dai).

4.1.1. Docking results for herbal medicines

According to statistics, licorice has the highest docking value in sorting, whether it was screened by ADME or not by ADME. The specific sorting results are as follows in Table 1.

Table 1.

Taking each of the six ways, the top 10 are summarized as follows.

	Original Value + All	Original Value + ADME	Dichotomies + All	Dichotomies + ADME	Relu + All	Relu + ADME
1	Chrysanthemum Flower	Licorice	Licorice	Licorice	Licorice	Licorice
2	Chinese Thorowax Root	Reishi Mushroom	Chinese Rose Flower	Reishi Mushroom	Chinese Rose Flower	Reishi Mushroom
3	Licorice	Sophora Root	Fiveleaf Gyno Stemma (Jiaogulan)	Chinese Salvia Root	Fiveleaf Gyno Stemma (Jiaogulan)	Chinese Rose Flower
4	Ephedra	Wolfberry Fruit	Cyathula Root	Chinese Rose Flower	Large Trifoliolious Bugbane Rhizome	Chinese Salvia Root
5	Myrrh	Myrrh	Large Trifoliolious Bugbane Rhizome	Corydalis yanhusuo W.T. Wang (Yan Hu Suo)	Cyathula Root	Corydalis yanhusuo W.T. Wang (Yan Hu Suo)
6	Loquat Leaf	Baikal Skullcap Root	Reishi Mushroom	Corydalis bungeana Turcz. (Ku Di Ding)	Reishi Mushroom	Corydalis bungeana Turcz. (Ku Di Ding)
7	Perilla Leaf	Gambir	Loquat Leaf	Chinese Date	Loquat Leaf	Chinese Date
8	Ginkgo Leaf	Amur Cork Tree	Myrrh	Myrrh	Chinese Holly Leaf	Amur Cork Tree
9	Reishi mushroom	Chinese Salvia Root	Chinese Holly Leaf	Sophora Root	Marlberry/Japanese Ardisia	Greater Celandine
10		Barbed Skullcap Herb	Marlberry/Japanese Ardisia	Greater Celandine	Myrrh	Myrrh

Notation. Relu = rectified linear unit; ADME = absorption, distribution, metabolism, and excretion.

4.1.2. Docking results for herbal medicines

The weighted mean was obtained for each of the three drugs tripartite based on the vector value of the drugs and the monarch (Jun), minister (Chen), assistant (Zuo), and courier (Shi) of the different drugs in the formula. When not weighted according to the monarch, minister, assistant, and courier, the highest docking value was for Jinhua Qinggan granules, followed by Lianhua Qingwen capsule and Xuebijing injection, regardless of the ranking according to that way. When weighted according to the monarch, minister, assistant, and courier, the highest docking value was for Jinhua Qinggan granules when ranked according to the three ways. The specific ranking results are as follows in Table 2.

Table 2.

The weighted mean was obtained for each of the three drugs tripartite based on the vector value of the drugs and the monarch (Jun), minister (Chen), assistant (Zuo), and courier (Shi) of the different drugs in the formula.

	Calculation method	Original value + ADME	Dichotomies + ADME	Relu + ADME
1	Original value	Jinhua Qinggan Granule	Jinhua Qinggan Granule	Jinhua Qinggan Granule
2		Lianhua Qingwen Capsules	Lianhua Qingwen Capsules	Lianhua Qingwen Capsules
3		Qingfei Paidu Decoction	Xuan Fei Bai Du Formula	Xuan Fei Bai Du Formula
4 44 4		Qingfei Paidu Decoction	Xuebijing Injection	Xuebijing Injection
5		Xuan Fei Bai Du Formula	Huashi Baidu Formula	Huashi Baidu Formula
6		Xuebijing Injection	Qingfei Paidu Decoction	Qingfei Paidu Decoction
1	Weighted value of a monarch, minister, assistant,and courier	Jinhua Qinggan Granule	Huashi Baidu Formula	Jinhua Qinggan Granule
2		Jinhua Qinggan Granule	Qingfei Paidu Decoction	Xuan Fei Bai Du Formula
3		Xuan Fei Bai Du Formula	Lianhua Qingwen Capsules	Xuebijing Injection
4		Lianhua Qingwen Capsules	Qingfei Paidu Decoction	Lianhua Qingwen Capsules
5		Qingfei Paidu Decoction	Xuan Fei Bai Du Formula	Qingfei Paidu Decoction
6		Huashi Baidu Formula	Jinhua Qinggan Granule	Huashi Baidu Formula

4.1.3. Graph of the results of the docking of herbal compounds

Using distance 6 as a criterion for whether the receptor protein binds to the compound, the location where the compound binds to the protein was determined. Then, the protein docking site for the compound was delineated, and the results are shown in Fig. 1.

Fig. 1.

This is a diagram of the docking for the Jinhua Qinggan granules with the neo-coronavirus protein, as shown in the diagram. The drugs in the Jinhua Qinggan granules, for the most part, act on the key targets of the neo-coronavirus protein.

4.1.4. Synergistic filtration results for Jinhua Qinggan Granules

The results of synergistic filtering of drugs for Jinhua Qinggan Granules are shown below. A total of 90 medicines are recommended in the eighth edition of the COVID-19 guidelines. The drug with the highest similarity to monarch Honeysuckle Flower (Jin Yin Hua) in the Jinhua Qinggan Granules is Humulus scandens (Lv Cao), and 7 of the first 20 drugs are in the COVID-19 Recommended Drugs, including Weeping Forsythia Capsule (Lian Qiao), Patriniae (Bai Jiang Cao), Coltsfoot Flower (Kuan Dong Hua), Perilla Leaf (Zi Su), Common Anemarrhena Rhizome (Zhi Mu), Golden Thread (Huang Lian), and Chinese Angelica (Dang Gui). The drug with the highest similarity to the monarch medicine of Weeping Forsythia Capsule is Chinese Magnolia Vine Fruit (Bei Wu Wei Zi), and 7 of the first 20 herbs are also in the Recommended Medicines for COVID-19, namely: Heartleaf Houttuynia Herb (Yu Xing Cao), Golden Thread (Huang Lian), Dahurian Angelica Root (Bai Zhi), Honeysuckle Flower (Jin Yin Hua), European Verbena Herb (Ma Bian Cao), Immature Orange Fruit (Zhi Shi), and Cassia Twig (Gui Zhi).

The drugs with the highest similarity to the ministerial medicines Bitter Apricot Seed (Ku Xing Ren), Gypsum (Shi Gao), and Ephedra (Ma Huang) are Willowleaf Rhizome (Bai Qian), Chinese Gall (Wu Bei Zi), and Perilla Seed (Zi Su Zi). A total of 13 drugs appear in the guidelines. The drugs with the highest similarity to the assistant drugs Baikal Skullcap Root (Huang Qin), Thunberg Fritillary Bulb (Zhe Bei Mu), Common Anemarrhena Rhizome (Zhi Mu), Great Burdock Achene (Niu Bang Zi), Sweet Wormwood Herb (Qing Hao), and Chinese Mint (Bo He) were Golden Thread (Huang Lian), Feather Cockscomb Seed (Qing Xiang Zi), Chinese Indigo (Liao Da Qing Ye), Sandalwood (Tan Xiang), Common Self-heal Fruit-Spike (Xia Ku Cao), and Wild Chrysanthemum Flower (Ye Ju Hua). A total of 30 drugs were in the COVID-19 Recommended Drugs list, and the courier drug with the highest similarity to Licorice Root (Gan Cao) was Fortune Eupatorium Herb (Pei Lan), of which 4 drugs appeared in the guidelines. The results are as follows, where the bold font indicates the drugs in the Jinhua Qinggan Granules, in each column in descending order of similarity, and the slanting typeface denotes the drugs that appear in the guide. The results are shown in Appendix 2.12

5. Discussion

5.1. Chinese medicine formulas for COVID-19 prevention and treatment

In the COVID-19 Treatment Protocol (Trial Version 8) issued by the National Health and Wellness Commission, a variety of TCM prescriptions are recommended, among which the efficacious six formulas, (i) Jinhua Qinggan Granules, (ii) Lianhua Qingwen Capsules, (iii) Xuebijing Injection, (iv) Qingfei Paidu Decoction, (v) Huashi Baidu Formula, and (vi) Xuanfei Baidu Formula, have made great contributions to the global fight against epidemics [21]. The formulas and their ingredients are presented in Table 3.13

Table 3.

This table shows the formulas and their ingredients and efficacy.

Name of Formula	Ingredients	Efficacy
Jinhua Qinggan Granules	Gypsum, Bitter almond/Ku Xing Ren (Amygdalus communis L.), Weeping Forsythia Capsule/Lian Qiao (Forsythia suspensa (Thunb.)Vahl), Ephedra/Ma Huang (Ephedra sinica Stapf.), Great Burdock Achene/Niu Bang Zi (Arctium lappa L.), Sweet Wormwood (Sweet Annie) Herb/Qing Hao (Artemisia annua L.), Japanese Honeysuckle Flower/Jin Yin Hua (Lonicerae japonicae Thunb.), Thunberg Fritillary Bulb/Zhe Bei Mu (Fritillaria thunbergii Miq.),Baikal Skullcap Root/Huang Qin (Scutellaria baicalensis Georgi),Chinese Mint/Bo He (Mentha canadensis L.),Common Anemarrhena Rhizome/Zhi Mu (Anemarrhena asphodeloides Bunge),Licorice Root/Gan Cao (Glycyrrhiza uralensis Fisch. ex DC.).	Dispersing wind and clearing lungs, clearing heat, and detoxifying.
Lianhua Qingwen Capsules	Weeping Forsythia Capsule/Lian Qiao (Forsythia suspensa (Thunb.)Vahl),Japanese Honeysuckle Flower/Jin Yin Hua (Lonicerae japonicae Thunb.), Bitter Apricot Seed/Xing Ren (Prunus armeniaca L.), Gypsum, Ephedra/Ma Huang (Ephedra sinica Stapf.), Chinese Rhubarb/Da Huang (Rheum undulatum var. longifolium C.Y.Cheng & T.C.Kao), Cablin Patchouli Herb/Guang Huo Xiang (Pogostemon cablin (Blanco) Benth.),Chinese Mint/Bo He (Mentha canadensis L.), Shield-fern (Male Fern) Rhizome/Guan Zhong (Dryopteris crassirhizoma Nakai), Rhodiola,/Hong Jing Tian (Rhodiola rosea L.), Isatis Root/Ban Lan Gen (Isatis tinctoria L.), Heartleaf Houttuynia Herb/Yu Xing Cao (Houttuynia cordata Thunb.), Licorice Root/Gan Cao (Glycyrrhiza uralensis Fisch. ex DC.).	Clearing away toxins, promoting lung circulation, and draining heat.
Xuebijing Injection	Red Peony Root/Chi Shao (Paeonia veitchii Lynch), Chinese Angelica/Dang Gui (Angelica sinensis (Oliv.) Diels), Chinese Salvia Root/Dan Shen (Salvia miltiorrhiza Bunge), Safflower flowers/Hong Hua (Carthamus tinctorius L.), Sichuan Lovage Rhizome/Xi Chuan Xiong (Ligusticum striatum DC.).	Clearing heat, removing toxins, and invigorating the blood circulation.
Qingfei Paidu Decoction	Seville Orange Fruit/Zhi Shi (Citrus aurantium L), Dried Tangerine (Mandarin Orange) Peel/Chen Pi (Citrus reticulata Blanco.), Cablin Patchouli Herb/Guang Huo Xian (Pogostemon cablin (Blanco) Benth.), Chinese Yam Rhizome/Shan Yao (Dioscorea opposita Thunb.), Licorice Root/Gan Cao (Glycyrrhiza uralensis Fisch. ex DC.).	Clearing heat and dampness, promoting lung circulation, relieving cough, and detoxifying.
Huashi Baidu Formula	Gypsum, Ephedra/Ma Huang (Ephedra sinica Stapf.), Bitter Apricot Seed/Xing Ren (Prunus armeniaca L.), Cablin Patchouli Herb/Guang Huo Xiang (Pogostemon cablin (Blanco) Benth.), Magnolia Bark/Hou Po (Magnolia officinalis Rehder & Wilson), Atractylodes Rhizome/Bai Zhu (Atractylodes macrocephala Koidz.), Fructus Tsaoko/Cao Guo (Fructus Tsaoko), Pinellia Tuber/Fa Ban Xia (Pinellia tuberifera Ten.), Poria mushroom/Fu Ling (Wolfiporia cocos F.A.Wolf), Chinese Rhubarb/Da Huang (Rheum undulatum var. longifolium C.Y.Cheng & T.C.Kao), Red Peony Root/Chi Shao (Paeonia veitchii Lynch), Milkvetch Root/Huang Qi (Astragalus membranaceus (Fisch.) Bunge), Pepperweed Seed/Ting Li Zi (Descurainia sophia (L.) Webb ex Prantl.).	Strengthening and clearing the lungs, resolving dampness, clearing heat, and detoxifying.
Xuanfei Baidu Formula	Gypsum, Ephedra/Ma Huang (Ephedra sinica Stapf.), Bitter Apricot Seed/Xing Ren (Prunus armeniaca L.), Coix Seed/Yi Yi Ren (Coix lacryma-jobi L.), Atractylodes Rhizome/Bai-zhu atractylodes (Atractylodes macrocephala Koidz.), Cablin Patchouli Herb/Guang Huo Xian (Pogostemon cablin (Blanco) Benth.), Sweet Wormwood HerPepperweed Seed/Ting Li Zi (Descurainia sophia (L.) Webb ex Prantl.),b/Qing Hao (Artemisia annua L.), Giant Knotweed Rhizome/Bian Xu (Polygonum aviculare L.), European Verbena Herb/Ma Bian Cao (Verbena officinalis L.), Reed Rhizome/Lu Gen (Phragmites communis Trin.), Pumelo (Pummelo) Peel/Hua Ju Hong (Citrus maxima Merr.), Licorice Root/Gan Cao (Glycyrrhiza uralensis Fisch. ex DC.).	Strengthening and clearing the lungs, resolving dampness, clearing heat, and detoxifying.

5.2. Jinhua Qinggan Granules

Jinhua Qinggan is an effective traditional Chinese medicine developed in 2009 in the fight against influenza A (H1N1). It is an innovative Chinese medicine that combines past knowledge on optimal remedies for typhoid and febrile disease with the new knowledge of modern Chinese medicine and the use of modern pharmaceutical technology to determine a choice of remedies. It is mainly used for fever, mild or no chills, red throat, sore throat, stuffy nose, runny nose, thirst, cough, or cough with phlegm. In a double-blind randomized controlled clinical trial for the treatment of influenza with wind-heat offending lung syndrome, this formula decreased the time and rate of fever reduction, ameliorated the clinical symptoms of TCM (with fever, head, and body pain, red throat, and sore throat as the main symptoms), increased the rate of viral transitions, and was confirmed to be safe and effective under conventional-dose treatment [22].

From the perspective of TCM clinical manifestations, H1N1 influenza is mainly a “heat toxin”, while COVID-19 is mainly a “damp toxin” epidemic, and although the etiology of the two is different, fever is their common characteristic [23]. The study of the pharmacological effect of Jinhua Qinggan Granules revealed that it decreases the mortality rate, prolongs the survival time, and decreased the amount of lung tissue lesions in a mouse model of influenza virus pneumonia [24]. Among the constituent flavors of this formula, various herbal extracts and ingredients such as honeysuckle flower, weeping forsythia capsule, licorice, and skullcap have anti-influenza virus or respiratory syncytial virus effects [[25], [26], [27], [28], [29]]. As a Chinese medicine recommended in the treatment plan, the antipyretic and antiviral effects of Jinhua Qinggan Granules can effectively ameliorate the clinical symptoms of COVID-19 patients.

Through a network pharmacology study, Peng et al. [30] found that Jinhua Qinggan Granules acted on PTGS2, TNF-α, NF-κB, IL-6, and CASP-8 targets and exerted anti-COVID-19 effects through Toll-like receptor signaling pathways.

Therefore, the group with the highest similarity ranking was based on the combination of Jinhua Qinggan Granules in the synergistic filtering results. The recommended grouping was: Chinese Gall (Wu Bei Zi), Willowleaf Rhizome (Bai Qian), Chinese Magnolia Vine Fruit (Bei Wu Wei Zi), Perilla Seed (Zi Su Zi), Sandalwood (Tan Xiang), Common Self-heal Fruit-Spike (Xia Ku Cao), Humulus scandens (Lu Cao), Golden Thread (Huang Lian), Wild Chrysanthemum Flower (Ye Ju Hua), Feather Cockscomb Seed (Qing Xiang Zi), Chinese Indigo (Liao Da Qing Ye), and Fortune Eupatorium Herb (Pei Lan). Because TCM emphasizes syndrome differentiation and treatment, it should be combined with the actual situation of patients in clinical practice.

5.3. Efficacy of single medicine

We first explored the rationality of our recommended drugs by combining the efficacy of the original drugs with the single drugs in our recommended drug combinations. The details of specific effects are presented in Table 4.14

Table 4.

This table shows the details of specific effects in Jinhua Qinggan Granules.

Jinhua Qinggan Granules	Efficacy
Gypsum	Clearing heat from the muscles, relieving irritation, and quenching thirst
Chinese Gall (Melaphis chinensis Bell)	Astringent to the lung, antiperspirant, astringent to the intestines, consolidating essence, stopping bleeding, detoxifying
Weeping Forsythia Capsule (Forsythia suspensa (Thunb.) Vahl.)	Clearing heat and detoxifying, subduing swellings, and dissipating nodules, wind-heat, and cold
Chinese Magnolia Vine Fruit (Schisandra chinensis (Turcz.) Baill.)	Invigorating the meridians, strengthening the spleen, and opening the stomach
Great Burdock Achene (Arctium lappa L.)	Dispersing wind-heat, promoting the lungs and pharynx to disperse nodules, resolving toxins, and subduing swellings.
Sandalwood (Santalum album L.)	Promoting the circulation of Qi, dispersing cold, and relieving pain
Honeysuckle Flower (Lonicerae japonicae Thunb.)	Clearing heat and toxins
Humulus Scandens (Humulus japonicus Siebold & Zucc.)	Clearing heat and detoxifying toxins, diuretic and laxative
Chinese Mint (Mentha canadensis L.)	Dispersing wind-heat, clearing the head and eyes, clearing the throat, clearing rashes, relieving depression
Wild Chrysanthemum (Chrysanthemum indicum L.)	Clearing heat and removing toxins, removing wind, and calming the liver
Thunberg Fritillary Bulb (Fritillaria thunbergii Miq.)	Clearing heat and resolving phlegm, lowering Qi, relieving cough, dispersing nodules, and subduing swelling
Feather Cockscomb Seed (Celosia argentea var. Plumosa)	Clearing liver fire, brightening eyes, and reducing cataracts
Bitter Almond (Amygdalus communis L.)	Expectorant, relieving cough, calming asthma, laxative, lowering Qi, and relieving paralysis
Willow Leaf Rhizome (Cynanchum stauntonii (Decne.)Schltr. ex Levl.)	Relaxation of the lungs and lowering of the Qi, decreasing phlegm, and stopping coughing
Ephedra (Ephedra sinica Stapf.)	Promoting sweating and relieving symptoms, promoting lung circulation and relieving asthma, inducing diuresis and reducing swelling.
Perilla Seed (Perilla frutescens L.)	Lowering Qi, eliminating phlegm, calming asthma, laxative
Sweet Wormwood Herb (Artemisia annua L.)	Clearing heat, relieving summer heat, removing steam, intercepting malaria
Common Self-heal Fruit-Spike (Prunella vulgaris L.)	Clearing the liver and the eyes, dispersing nodules, and detoxifying
Skullcap (Scutellaria baicalensis Georgi)	Clearing heat and fire, drying dampness and detoxifying, stopping bleeding, and calming the fetus
Golden Thread (Coptis chinensis Franch.)	Clearing heat and fire, drying dampness, detoxifying
Common Anemarrhena Rhizome (Anemarrhena asphodeloides Bunge)	Clearing away heat and fire, nourishing Yin, moistening dryness, quenching thirst, and relieving irritation
Dyer's Knotweed/Chinese Indigo (Polygonum tinctorium Aiton)	Clearing heat and removing toxins, cooling the blood, and eliminating blemishes
Licorice Root (Glycyrrhiza uralensis Fisch. ex DC.)	Benefiting the vital energy, relieving urgency and pain, moistening the lungs and relieving cough, removing fire and detoxifying, harmonizing various herbs
Fortune Eupatorium Herb (Eupatorium fortunei Turcz.)	Relieving summer heat and dampness, removing toxins, and harmonizing

Based on the efficacy of each medicine, the efficacies of the recommended drugs are roughly similar to those of the original drugs in the formula. As a group of proprietary Chinese medicine prescriptions, Jinhua Qinggan Granules can be used for fever, cough, and malaise caused by viral infection, in addition to being used for the routine treatment of novel coronavirus pneumonia.

5.4. Modern pharmacology

The results of the analysis of the rationality of our recommended drugs according to modern pharmacology show in Table 5.

Table 5.

This table shows modern pharmacological studies for our recommended drugs.

Medicines	Modern pharmacology
Chinese Gall	The inhibitory effect of Chinese Gall on the influenza virus was demonstrated by its ability to reduce syncytial virus replication, decrease apoptosis, and inhibit influenza virus neuraminidase activity [32]. Zhou et al. observed therapeutic effects on influenza virus-induced acute lung injury in mice after treatment with Chinese Gall ester. An extract of Chinese Gall decreased the activation of Toll-like receptor 4, inhibited the downstream MyD88-dependent transduction pathway, decreased the transcriptional production of inflammatory factors, reduced lung inflammation, and slowed the process of acute lung injury [33]
Willow Leaf Rhizome	Pharmacological studies have shown that Willow Leaf Rhizome extract has anti-cough, expectorant, and anti-inflammatory effects, as well as analgesic and anti-thrombotic effects [34,35].
Chinese Magnolia Vine Fruit	Chinese Magnolia Vine Fruit directly excites the respiratory center and increases the respiratory rate and amplitude, and its ether extract exerted coughing and expectorant effects. The volatile oil suppresses coughing, and its acidic extract exerted an obvious expectorant effect [36].
Perilla Seed	Possesses anti-oxidant, anti-allergy, immune-boosting, intelligence-enhancing, blood lipid-lowering, and stress-alleviation properties [[37], [38], [39], [40]].
Sandalwood	Sharma et al. [41] proved that sandalwood oil, α-sandalonol, and β-sandalonol had significant anti-inflammatory effects, and revealed that their anti-inflammatory mechanism involved inhibiting the production of cytokines and prostaglandin E2 induced by lipopolysaccharide. The anti-viral, anti-inflammatory, and anti-pyretic effects of sandalwood volatile components may be effective in the prevention and treatment of COVID-19 and relief of fever symptoms, and their aromatic properties assist in relieving patient pain and anxiety [42].
Common Self-heal Fruit-Spike	Modern pharmacological research has confirmed that the main components in the fruit of Common Self-heal are triterpenes, sterols, flavonoids, and organic acids, which exhibit anti-tumor, anti-inflammatory, anti-viral, immunity regulation, hypotension, hypoglycemia, and hypolipidemia activity [43].
Humulus scandens	Humulus scandens has antioxidant and anti-inflammatory capability and is now widely used in the treatment of tuberculosis, dysentery, and chronic colitis (Zhang D et al., 2021).
Golden Thread	Golden Thread showed significant inhibition in vitro against Gram-positive and -negative bacteria. It is a broad-spectrum antibacterial drug due to the berberine it contains, with a satisfactory antibacterial effect against pneumococcal Mycobacterium pneumonia, Mycobacterium pertussis, Mycobacterium tuberculosis, and some fungi. It also has an inhibitory effect on influenza A, B, and C viruses. Golden Thread also has significant antiviral effects. Ma et al. [44]found that the aqueous extract of Golden Thread exerted antiviral effects by inhibiting influenza virus RNA polymerase. In the treatment of lobar pneumonia, Golden Thread powder was taken internally 4–6 times a day in 23 cases, and fever was reduced in an average of 2.9 days.
Wild Chrysanthemum Flower	1. Anti-hypertensive effect 2. Role in the cardiovascular system. Wild chrysanthemum flower can directly protect myocardium and inhibit cardiomyocyte fibrosis. It can effectively inhibit the activity of the renin-angiotensin-aldosterone system and the sympathetic nervous system in rats with pressure-overloaded ventricular remodeling; reduce the production of angiotensin II (Ang II), tumor necrosis factor-α (TNF-α), and aldosterone (ALD); and inhibit myocardial hypertrophy and ventricular remodeling. 3. Inhibits a variety of pathogenic bacteria such as dysentery bacillus and typhoid bacillus. A high concentration also has a certain degree of inhibition on a variety of skin fungi. It delays the formation of lesions on human embryonic kidney or human liver and lung primary monolayer epithelial cells caused by ECHO11 virus, herpes virus, and the Kyoto 68-1 strain of influenza virus. 4. Wild chrysanthemum decoction promotes the engulfment of Staphylococcus aureus [45].
Chinese Indigo	1. Chinese Indigo inhibits the B encephalitis virus, mumps virus, influenza virus, and other pathogens. The indole base extracted from Chinese Indigo leaves also showed an antiviral effect in tissue culture experiments, inhibited influenza virus-induced pneumonia in mice, and significantly reduced viral lesions. 2. The antipyretic and anti-inflammatory effects of Chinese Indigo decoction by gavage significantly decreased the body temperature of cholera and typhoid fever induced by mixed vaccines. It also reduced or accelerated the regression of formaldehyde foot swelling in rats and decreased the local inflammatory skin reaction and capillary permeability induced by toluene [45].
Feather Cockscomb Seed	In Indian folk medicine, Celosia argentea is used to treat diabetes, jaundice, gonorrhea, wounds, and fevers [46].
Fortune Eupatorium Herb	The volatile oil of Fortune Eupatorium Herb contains polyphyllin, neroli acetate, and other components that can effectively inhibit influenza viruses [47].

5.5. Drug pairs

An herbal pair is the main form of a combination of herbs in TCM, and they are widely used for the treatment of diseases. They can also assist us in increasing our understanding of the compatibility of the components in TCM, thus improving the curative effects [31]. A TCM preparation is the main form of TCM, and it is produced under the guidance of TCM syndrome differentiation and treatment, which is highly scientific.

At present, due to the limitations of the experimental conditions required for in vivo and ex vivo studies on SARS-CoV-2, virtually assisted drug design is used for the initial screening of anti-COVID-19 drugs, which is technically advantageous. The use of common components identified from various clinically effective formulations as a vehicle for anti-SARS-CoV-2-related experimental studies can facilitate the development and application of anti-coronavirus drugs derived from TCM [8].

Therefore, we explain the rationality of our recommended drug combinations in terms of the pairing of drugs shown in Table 6.

Table 6.

This table illustrates the rationality of our recommended drug combinations by the relationships between drugs.

Medicines	Modern pharmacology
Chinese Gall	With Schizandra berries for deficiency of the lung and prolonged cough with phlegm and heat.
Willow Leaf Rhizome	1. With Almond, Spirulina, and Perilla seeds for cough caused by the upward flow of lung Qi. 2. With Perilla seeds to treat asthmatic cough due to congestion and phlegm.
Chinese Magnolia Vine Fruit	With Chinese Gall, for deficient lungs with prolonged cough, phlegm, and heat.
Perilla Seed	With Schizandra berries to resolve phlegm and relieve cough.
Fortune Eupatorium Herb	With Wild Chrysanthemum flowers to treat summer exopathia, fever, and headache.

In this study, we aimed to develop a collaborative filtering approach to signaling drug combinations that are similar to the Jinhua Qinghua granules as potential therapeutic treatments for treating COVID-19. The results have been evaluated by herbal medicine experts’ domain knowledge. But due to experimental and time limitations, more prescriptions were not considered. In the later stage, we will conduct a mix-way of dry-lab (computational approaches) and wet-lab (proteins test) research based on the herbs data. Then under the observation of clinical trials.

6. Conclusion

Based on molecular docking and synergistic filtration techniques, this study was conducted to analyze the ability of the compound components contained in Jinhua Qinggan Granules to bind with neo-coronavirus proteins. Thus, we initially explored the possible mechanism of action of Jinhua Qinggan Granules for the prevention and treatment of COVID-19. This study may provide new ideas and methods for further identification of anti-COVID-19 drugs and recommendations for new Chinese herbal formulations that incorporate active ingredients of Chinese medicine.

Author contribution statement

Ruiyuan Yao, FanYang, Xin Wang: Conceived and designed the experiments; Analyzed and interpreted the data; Performed the experiments; Wrote the paper.

Qiang Jiao, Jianing Liu, Hong Yu: Performed the experiments; Analyzed and interpreted the data.

Xiushan Nie, Hongkai Li, Fuzhong Xue: Performed the experiments.

Funding statement

Fan Yang was supported by Chongqing University of Posts and Telecommunications [2021YFF0704100], Natural Science Foundation of Shandong Province [2020YFC2003500].

Data availability statement

Data included in article/supp. material/referenced in article.

Declaration of interest’s statement

The authors declare no competing interests.