Table 1.

Description of the studies included in the review, including methods or software applied for in silico discovery of anti-COVID-19 drugs.

Title	Reference	Method/software or databases applied	Drug target	Lead candidate	Experimental technique
Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses	Alzahrani et al. [13]	Chemical synthesis/Cu(I)-catalyzed click 1,3-dipolar cycloaddition reaction	RNA-dependent RNA polymerase	Bis-(1,2,3-triazole-sulfadrug hybrids) carrying benzimidazole moiety (4b and 4c) against RNA-dependent RNA polymerase	In vitro antiviral activity
		Molecular docking/MOE 2019	Spike protein S1 main protease (3CLpro)	4c against SARS-CoV-2 spike protein
		Physicochemical properties and drug-likeness test/molinspiration and Mol-Soft software	2′-O-methyltransferase (nsp16)	4b and 4c against SARS-CoV-2 3CLpro and nsp16
Chemical-informatics approach to COVID-19 drug discovery: the exploration of important fragments and data mining based prediction of some hits from natural origins as main protease (Mpro) inhibitors	Ghosh et al. [14]	QSAR/SiRMS tools	SARS-CoV-2 Mpro	Diazole, furan, and pyridine	None
Computational investigation of potent inhibitors against SARS-CoV-2 2′-O-methyltransferase (nsp16): structure-based pharmacophore modeling, molecular docking, molecular dynamics simulations, and binding free energy calculations	Shi et al. [15]	Pharmacophore modeling/phase	SARSCoV-2 2′-O-methyltransferase (nsp16)	C1 with CAS ID 1224032-33-0 and C2 with CAS ID 1224020-56-7	None
		Pharmacophore-based virtual screening/phase
		Molecular docking/glide
		Molecular dynamics simulation/Gromacs 2021
Discovery of new drug indications for COVID-19: A drug repurposing approach	Kumari et al. [16]	Chemical-chemical and chemical-protein interaction/STITCH database	SARS-CoV-2 Mpro	Doxorubicin and buedesonide (pulmicort)	None
		Randomization test/SWISSADME
		Molecular docking/Autodock 4 tool
Discovery of novel TMPRSS2 inhibitors for COVID-19 using in silico fragment-based drug design, molecular docking, molecular dynamics, and quantum mechanics studies	Alzain et al., [17]	Homology modeling using Schrodinger	TMPRSS2	Combine 1, 2, and 3	None
		Program
		High-throughput virtual screening
		Molecular docking
		Molecular dynamics simulation
Exploring the treatment of COVID-19 with Yinqiao powder based on network pharmacology	Lin et al., [18]	Virtual screening	SARS-CoV-2	Yinqiao powder	SPR assay
		Protein-protein interaction network construction
		Molecular docking
High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors	Zhao et al., [19]	Virtual screening	SARS-CoV-2 papain-like protease (PLpro)	YM155	Cell-based assays
			SARS-CoV-2 main protease
In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors	Ibrahim et al., [20]	Molecular docking	SARS-CoV-2 main protease	Salvianolic acid A and curcumin	None
		Molecular dynamics simulation
		Drug-likeness
		Protein-protein interaction
In silico evaluation of prospective anti-COVID-19 drug candidates as potential SARS-CoV-2 main protease inhibitors	Ibrahim et al., [21]	Molecular docking	SARS-CoV-2 main protease	TMC-310911 and ritonavir	None
		Molecular dynamics simulation
In silico investigation of ACE2 and the main protease of SARS-CoV-2 with phytochemicals from Myristica fragrans (Houtt.) for the discovery of a novel COVID-19 drug	Ongtanasup et al., [22]	Molecular docking	ACE2 and the main protease of SARS-CoV-2	Myristica fragrans compounds	None
		Molecular dynamics simulation
		Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction
In silico screening of natural products isolated from Mexican herbal medicines against COVID-19	Rivero-Segura and Gomez-Verjan [23]	Virtual screening	SARS-CoV-2 proteins	Cichoriin	None
		Molecular docking
		Pharmacokinetic assessment
In silico screening of novel TMPRSS2 inhibitors for treatment of COVID-19	Wang et al., [24]	Homology modeling and virtual screening	TMPRSS2	Lumacaftor and ergotamine	None
		Molecular dynamics simulation
In silico screening of potential anti-COVID-19 bioactive natural constituents from food sources by molecular docking	Xu et al., [25]	Virtual screening	SARS-CoV-2 CLpro	Red wine, Chinese hawthorn, and blackberry	None
		Molecular docking	Humans ACE2
		ADME analysis
		Drug likeness
Inhibitory activity of FDA-approved drugs cetilistat, abiraterone, diiodohydroxyquinoline, bexarotene, remdesivir, and hydroxychloroquine on COVID-19 main protease and human ACE2 receptor: A comparative in silico approach	Shahabadi et al., [26]	Molecular docking	SARS-CoV-2 main protease	Cetilistat, abiraterone, di-iodo hydroxyquinoline, and bexarotene	None
		Molecular dynamics simulation	ACE2
In-silico drug repurposing and molecular dynamics puzzled out potential SARS-CoV-2 main protease inhibitors	Ibrahim et al., [27]	Molecular docking	SARS-CoV-2 main protease	DB02388 and cobicistat	None
		Molecular dynamics simulation
Investigating the active compounds and mechanism of HuaShi XuanFei formula for prevention and treatment of COVID-19 based on network pharmacology and molecular docking analysis	Wang et al., [28]	Virtual screening	3C-like (3CL) protease hydrolase and angiotensin-converting enzyme 2 (ACE2)	HuaShi XuanFei	None
		Molecular interaction networks using Cytoscape		Formula (HSXFF)
		Protein–protein interaction (PPI) network construction
		Gene ontology enrichment analysis and KEGG pathway analysis
		Molecular docking
		Molecular dynamic (MD) simulation
Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: an in silico molecular modeling approach in battling the COVID-19 outbreak	Shawan et al., [29]	Creation of flavonoids library	ACE2 of human host and Mpro/3CLpro and PLpro of SARS-CoV-2	Luteolin and abyssinone II	None
		Drug likeness/pharmacophore and ADMET profile analysis
		Virtual screening and molecular docking
		Molecular dynamics simulation
		ADMET profile analysis
Marine algal antagonists targeting 3CL protease and spike glycoprotein of SARS-CoV-2: a computational approach for anti-COVID-19 drug discovery	Arunkumar et al., [30]	Molecular docking tools (AutoDockTools)	3CL protease and spike glycoprotein of SARS-CoV-2	k-Carrageenan, laminarin, eckol, trifucol, and b-D-galactose	None
		Molecular dynamic simulation, ADMET, and density functional theory calculations
MCCS: a novel recognition pattern-based method for fast-track discovery of anti-SARS-CoV-2 drugs	Feng et al., [31]	Virtual screening by MCCS	3CLPro in SARS-CoV-2	Lopinavir, tenofovir disoproxil, fosamprenavir, and ganciclovir	None
				Peramivir and zanamivir
				Sofosbuvir
Molecules against Covid-19: an in silico approach for drug development	Bharti and Shukla [32]	Molecular docking	SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp)	Ellipticine, ecteinascidin, homo harringtonine, dolastatin 10, halichondrin, and plicamycin	None
		Absorption, distribution, metabolism, and excretion (ADME) analysis
		Drug-likeness test
Multidimensional in silico strategy for identification of natural polyphenols-based SARS-CoV-2 main protease (Mpro) inhibitors to unveil a hope against COVID-19	Adem et al., [33]	Quantum mechanics	SARS-CoV-2 main protease (Mpro)	Hesperidin, rutin, diosmin, and apiin	None
		Molecular docking
		Molecular dynamic simulations
Multi-step in silico discovery of natural drugs against COVID-19 targeting main protease	Elkaeed et al., [34]	Molecular similarity detection using	SARS-CoV-2 main protease	Luteoside C, kahalalide E, and streptovaricin B	None
		Discovery Studio software
		Molecular fingerprint detection using
		Discovery Studio software
		Docking studies using MOE.14 software
		Toxicity studies using discovery
		Studio 4.0
		Molecular dynamics (MD) simulations using the GROningen MAchine
Natural-like products as potential SARS-CoV-2 Mpro inhibitors: in-silico drug discovery	Ibrahim et al., [35]	Virtual screening of MolPort database	SARS-CoV-2 Mpro	Four bis [1, 3] dioxolo pyran-5-carboxamide derivatives	None
		Molecular docking
		Molecular
		Dynamics (MD) simulations
		Drug-likeness predictions
Potent toxic effects of Taroxaz-104 on the replication of SARS-CoV-2 particles	Rabie [37]	Computational molecular docking studies	RNA-dependent RNA polymerase (nCoV-RdRp)	Taroxaz-104	In vitro anti-COVID-19 bioactivities of Taroxaz-104
		In vitro anti-COVID-19 bioactivities of Taroxaz-104
Promising terpenes as SARS-CoV-2 spike receptor-binding domain (RBD) attachment inhibitors to the human ACE2 receptor: an integrated computational approach	Muhseen et al., [38]	Structure-based virtual screening	SARS-CoV-2 spike receptor-binding domain (RBD)	NPACT01552, NPACT01557 and NPACT00631	None
		Molecular dynamics (MD) simulation
Rational design of potent anti-COVID-19 main protease drugs: an extensive multi-spectrum in silico approach	Ahmad et al., [36]	Structure-based virtual screening (SBVS) of ASINEX antiviral library	SARS-CoV-2 MPro	SCHEMBL 12616233, SCHEMBL 18616095, and SCHEMBL 20148701	None
		Drug-likeness and lead likeness annotations
		Pharmacokinetics analysis
		Molecular dynamics (MD) simulations
Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: in silico drug discovery study	Ibrahim et al., [39]	Virtual screening	SARS-CoV-2 Mpro	PubChem-129-716-607 and pubChem-885-071-27	None
		Molecular docking
		Molecular dynamics simulations
		Drug-likeness evaluation
Screening, molecular simulation and in silico kinetics of virtually designed Covid-19 main protease inhibitors	Aleissa et al., [40]	Virtual screening	SARS-CoV-2 Mpro	HIT-1 and HIT-2	None
		Molecular docking
		Molecular dynamics (MD) simulations
		ADME calculations
Structure-based screening of natural product libraries in search of potential antiviral drug leads as first-line treatment for COVID-19 infection	Rao and Shetty [41]	Virtual screening	SARS-CoV NSP12 polymerase	12,28-Oxa-8-hydroxy-manzamine A	None
		Pharmacokinetic and pharmacodynamics properties analysis
		Molecular docking
		Molecular dynamic simulations
Targeting SARS-CoV-2 RNA-dependent RNA polymerase: an in silico drug repurposing for COVID-19 [version 1; peer review: 2 approved]	Baby et al., [42]	Molecular docking	SARS-CoV-2 RNA-dependent RNA polymerase	Pitavastatin, ridogrel, and rosoxacin	None
		Molecular dynamics simulation
Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development	Pandey et al., [43]	Molecular docking	SARS-CoV-2 spike protein	Fisetin, quercetin, and kaempferol	None
		Molecular dynamics (MD) simulation
		ADME analysis
The potential effects of clinical antidiabetic agents on SARS-CoV-2	Qu et al., [44]	Molecular dynamics simulation	SARS-CoV-2 Mpro	Repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin	In vitro study
		Molecular docking study
		In vitro study
Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms	Quimque et al., [45]	Molecular docking	SARS-CoV2 PLpro	Three fumiquinazoline alkaloids scedapin C, quinadoline B, and norquinadoline A	None
		Molecular dynamics simulation	Chymotrypsin-like protease (3CLpro)	The polyketide iso-chaetochromin
		Drug-likeness, ADME, and toxicity prediction	SARS-CoV-2 RdRp	The terpenoid 11a-de hydroxy isoterreulactone A
			SARS-CoV-2 nsp15
			SARS-CoV-2 S protein (spikes)