Structural modification of aspirin to design a new potential cyclooxygenase (COX-2) inhibitors

Abstract

Aspirin (Asp) is one of the most important and ancient member of nonsteroidal anti-inflammatory drugs (NSAID), commonly used in medication of fever, pain and inflammation. It can inhibit the synthesis of prostaglandin by blocking the cyclooxygenase (COX). Attempts have been taken to analyze aspirin together with some of its modified derivatives applying quantum mechanical calculations in order to compare their physicochemical and biochemical properties. Density functional theory (DFT) with B3LYP/6-31G (d, p) basis set has been employed to elucidate their thermal, molecular orbital, equilibrium geometrical properties in gas phase. Molecular docking and nonbonding interactions have been performed against human cyclooxygenase-2 protein 5F1A to investigate the binding affinity and mode(s) of newly designed aspirin derivatives. ADMET prediction has been utilized to compare the absorption, metabolism, and carcinogenic properties of new derivatives with parent drug (Asp). Thermal and geometrical results support the thermochemical stability and equilibrium geometry of all the structures. From the molecular docking simulation, most of the derivatives exhibited better binding affinity than parent drug (Asp) with the receptor protein (5F1A). ADMET prediction disclosed the improved pharmacokinetic properties with lower acute oral toxicity of some derivatives. Based on quantum chemical, molecular docking and ADMET analysis, this investigation can be useful to understand the physicochemical and biochemical/biological activities of Asp and its modified derivatives to search a new antipyretic analgesic drug.

Electronic supplementary material

The online version of this article (10.1007/s40203-020-0053-0) contains supplementary material, which is available to authorized users.

Introduction

Structural modification is one of the important way to design a new potential drug (Li et al. 2004). Computer-aided drug designing methods are popularly used in structure-based drug design (Åqvist et al. 1994). Aspirin (Asp) or acetylsalicylic acid is a member of nonsteroidal anti-inflammation drug (NSAID) and commonly used as analgesic, antipyretic and anti-inflammation agent (H. and Joseph 2000; Husain et al. 2015; Koohshekan et al. 2016). It plays an important role in the treatment of cancer (Cuzick et al. 2009; Patrignani and Patrono 2016; Thun et al. 1991, 2012) heart attack, strokes (McNeil et al. 2018b; Ridker et al. 2005; Seshasai et al. 2012) and cardiovascular diseases (Baigent et al. 2009; McNeil et al. 2018a; Richman and Owens 2017). It suppress the prostaglandin synthesis by blocking cyclooxygenase (COX-1 and COX-2) (Catella-Lawson et al. 2001; Saxena et al. 2013) and also work as antiplatelet agent (Lewis Jr et al. 1983). Inhibition of COX-1 increase the possibility gastrointestinal problems where COX-2 inhibition effective against pain, fever and inflammation (Crofford 1997; Glaser 2001; Insel 1996). Some of the COX-2 inhibitor drugs are also responsible for heart attack and stroke (Mukherjee et al. 2001). Asp has some common adverse effects based on the nature of physical condition and dose limitation. The common adverse effects include asthma, ulcers, kidney diseases, stomach upset, stomach bleeding, reye syndrome, swelling of skin tissues and ringing in the ears occur due to proper dose differentiation (Silagy et al. 1993; Sostres et al. 2010). Previously, a few studies also reported the computational investigation of Asp (Datt et al. 2012; El-Shahawy 2014; Khan et al. 2015; Marjan et al. 2014) and its modification (Plano et al. 2016). Attempt has taken to optimize some newly designed derivatives and to investigate their structural, chemical, and biological properties.

Recently, it is proven that the modification of drugs by inserting some alkyl, alkoxy, amino, halogen, and hydroxyl groups improving drug performance (Juillerat‐Jeanneret and Schmitt 2007; Li et al. 2004; Uzzaman and Hoque 2018). Herein, we reported the optimization of Asp and its modified derivatives to investigate their biochemical behaviour on the basis of quantum mechanical approach. The free energy, enthalpy, dipole moment, electrostatic potential, equilibrium geometry, vibrational frequency, HOMO–LUMO gap, hardness, softness, and chemical potential have been calculated. Molecular docking and nonbonding calculation have also been performed to understand the binding affinity, mode(s) and interaction between drugs and amino acid residues of human prostaglandin synthase protein (5F1A). All the derivatives showed improved thermodynamic stability, and few of them have better binding affinity, reactivity and nonbonding interactions. From the regarding quantum chemical studies, we are assuming that, some of the designed compounds have better cyclooxygenase inhibition capability than the parent drug (Asp).

Computational details

Geometry optimization

In computer aided drug design, quantum mechanical methods are widely used to predict thermal, molecular orbital, and molecular electrostatic potential properties (Gleeson and Gleeson 2009). Initial geometry of Aspirin (Asp) was taken from the online structure database named ChemSpider (Pence and Williams 2010). Geometry optimization and further modification of all structures were carried out using Gaussian 16 program (Frisch et al. 2016). Density functional theory (DFT) with Becke’s (B) (Becke 1988) three-parameter hybrid model, Lee, Yang and Parr’s (LYP) correlation functional (Lee et al. 1988) under Pople’s 6-31 g (d, p) basis set has been employed for geometry optimization (Kruse et al. 2012). Initial optimization of all compounds was performed in the gas phase. Dipole moment, electronic energy, enthalpy, free energy, electrostatic potential, vibrational frequencies, bond distances and angles are calculated for all the compounds.

Frontier molecular orbital HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) were calculated at the same level of theory. For each of the compound, HOMO–LUMO energy gap $\left(\mathrm{\Delta }E\right)$, hardness (η), softness (S) and chemical potential were calculated from the energies of HOMO and LUMO by considering Parr and Pearson interpretation (Calais 1993; Pearson 1995) of DFT and Koopmans theorem (Pearson 1986) on the correlation of ionization potential (I) and electron affinities (E) with HOMO and LUMO energy (ε). The following equations are used to calculate hardness (η), softness (S), and chemical potential (μ);

$$\text{Gap}\left(\mathrm{\Delta }\text{E}\right)=\left[\epsilon \text{LUMO}-\epsilon \text{HOMO}\right];\eta =\frac{\left[\epsilon \text{LUMO}-\epsilon \text{HOMO}\right]}{2};\mu =\frac{\left[\epsilon \text{LUMO}+\epsilon \text{HOMO}\right]}{2};\text{S}=\frac{1}{\eta }$$

Preparation of receptor protein

The 3D crystal structure of salicylate bounded human cyclooxygenase-2 (PDB ID: 5F1A) was obtained in pdb format from online protein data bank (PDB) database (Lucido et al. 2016). All hetero atoms and water molecules were eliminated using PyMol (version 1.3) software packages (DELANO 2002). Energy minimization of the protein implemented by Swiss-Pdb viewer software (version 4.1.0) (Guex and Peitsch 1997).

Molecular docking simulation, analysis and visualization

Molecular docking simulation was performed to calculate the binding affinity, binding mode(s) and to understand the mechanism of the prostaglandin H2 (PGH2) inhibition by newly designed analogues (Seeliger and De Groot 2010). The optimized structures were subjected for molecular docking study against human prostaglandin synthase protein (5F1A) considering the protein as macromolecule and the drug as ligand (Table 1). Finally, rigid docking simulation was performed by PyRx software (version 0.8) considering the center grid box size 65.2803, 76.6322 and 56.3368 Å along x, y and z directions respectively (Dallakyan and Olson 2015). After docking, both the protein and ligand structures were saved in pdb format for further non-bonding interactions and hydrogen bond surface calculation. Accelrys Discovery Studio (version 4.1) software was utilize to analyze and visualize the docking result (Accelrys Discovery Studio version 4.1 2017).

Table 1.

Molecular formula, electronic energy, enthalpy, Gibb’s free energy in Hartree and dipole moment (Debye) of Aspirin (Asp) and its modified derivatives

Name	Molecular formula	Molecular weight	Electronic energy	Enthalpy	Gibb’s free energy	Dipole moment
Asp	C9H8O4	180.158	− 648.543	− 648.530	− 648.582	4.456
A1	C8H7NO4	181.145	− 660.825	− 660.813	− 660.863	4.279
A2	C9H5F3O4	234.129	− 946.262	− 946.247	− 946.304	6.658
A3	C9H9NO4	195.172	− 703.899	− 703.885	− 703.941	3.375
A4	C10H10O4	194.184	− 687.8367	− 687.822	− 687.878	4.808
A5	C10H10O5	210.183	− 763.035	− 763.019	− 763.077	4.607
A6	C10H10O4	194.184	− 687.837	− 687.823	− 687.879	4.883
A7	C10H10O5	210.183	− 763.038	− 763.023	− 763.080	5.060
A8	C9H7FO4	198.148	− 747.781	− 747.767	− 747.821	3.681
A9	C9H7FO4	198.148	− 747.782	− 747.769	− 747.822	3.578
A10	C10H9FO4	212.174	− 787.077	− 787.062	− 787.119	3.988
A11	C10H9FO4	212.174	− 787.076	− 787.061	− 787.119	4.175
A12	C11H11NO5	237.209	− 856.510	− 856.492	− 856.557	4.814
A13	C11H11NO5	237.209	− 856.512	− 856.494	− 856.558	7.049
A14	C10H7F3O4	248.155	− 985.572	− 985.556	− 985.617	3.265
A15	C10H7F3O4	248.155	− 985.572	− 985.555	− 985.617	3.008
A16	C9H9NO4	195.172	− 703.885	− 703.871	− 703.925	5.150
A17	C9H9NO4	195.172	− 703.889	− 703.875	− 703.929	5.903
A18	C10H7F3O5	264.155	− 1060.784	− 1060.767	− 1060.831	2.365
A19	C9H8O5	196.157	− 723.758	− 723.744	− 723.798	5.260
A20	C9H9NO4	195.172	− 703.872	− 703.858	− 703.913	5.341
A21	C9H8O5	196.157	− 723.746	− 723.732	− 723.786	6.230

ADMET prediction

AdmetSAR online database was utilized to predict absorption, distribution, metabolism, excretion, and toxicity (ADMET) of Aspirin and its modified derivatives (Cheng et al. 2012).

Result and discussion

Thermochemical analysis

Simple modification of drug can improve the physicochemical and binding properties (Uzzaman et al. 2019; Uzzaman and Uddin 2019). Free energy is an important criterion to predict the spontaneity of a chemical reaction and thermal stability of any chemical species (Cohen and Benson 1993). The insertion of some electron rich and deficient functional groups improved the thermal, molecular orbital and medicinal properties (Li et al. 2004). Here, all the compounds have negative free energy and enthalpies which indicate the spontaneous binding possibility without any external energy (Garbett and Chaires 2012). The free energy of Aspirin − 648.582 Hartree, where A18 shows the highest free energy (− 1060.831 Hartree) due to the addition of –CF₃ and –OCH₃ function group. All the modified derivatives have higher negative free energy than parent drug which suggesting the improved thermal and structural properties (Fig. 1).

Fig. 1.

Chemical structures of aspirin (Asp) and its modified derivative

Some of the derivatives have improved dipole moment which can enhance the polarity, binding affinity, hydrogen bond formation and non-bonded interactions with the receptor protein (Lien et al. 1982). The dipole moment of Asp is 4.456 Debye where A13 shows the highest dipole moment (7.049 Debye) due to the presence of electronegative nitrogen and oxygen atoms in the structure which can contribute for better binding with the receptor protein (Table 3).

Table 3.

Binding affinity and nonbonding interactions of all compounds with the receptor protein (5F1A) after molecular docking

Name	Binding affinity (kcal/mol)	Residues in contact	Interaction type	Distance (A°)
Asp	− 6.5	Trp387	H	2.79557
		His207	C	2.66356
		His386	C	2.29112
		Ala202, Gln203	Aps	5.09399
		Ala202	PA	5.45948
		Leu391	PA	5.33603
A1	− 6.5	Thr206	H	2.34497
		Tyr3385	H	2.58050
		His207	C	2.50002
		His386	C	2.49235
		Ala202, Gln203	Aps	5.10774
		Ala202	PA	5.45824
		Leu391	PA	5.35102
A2	− 7.2	Thr206	H	2.28898
		His207	C	2.41546
		His386	C, X	2.60499
		His386	C	2.33544
		Try385	X	3.09809
		Try385	X	3.67359
		Ala202, Gln203	Aps	5.11476
		Leu391	PA	5.42889
A3	− 6.8	His39	H	2.76148
		Gln461	H	2.23460
		Gln461	H	2.05290
		Glu465	H	2.88758
		Gln42	C	3.08630
		Val46	A	5.21339
		Try130	PA	5.37151
		Leu152	PA	5.39374
		Pro153	PA	5.26603
A4	− 6.7	Thr206	H	2.17039
		Ala202	H	2.89058
		His207	C	2.41971
		His386	C	2.37356
		Ala202, Gln203	Aps	5.05199
		Ala199	A	3.62191
		Leu390	A	4.24551
		Leu391	A	4.03214
		Ala202	PA	5.38331
		Leu391	PA	5.48433
A5	− 6.6	His39	H	2.64970
		Tyr130	H	2.20458
		Gln461	H	2.86954
		Gln461	H	2.47085
		Gly45	C	2.69739
		Val46	PA	5.30921
		Cys47	PA	5.14070
		Pro153	PA	4.15687
A6	− 6.4	Thr206	H	2.15323
		His207	H	2.87399
		Try385	H	2.12129
		His207	C	2.92525
		His388	C	2.84125
		Ala202, Gln203	Aps	4.58196
		Ala199	A	3.95399
		Leu390	A	4.18815
		Leu391	A	4.25946
		Ala202	PA	4.87291
A7	− 6.5	Thr206	H	2.05528
		His388	C	2.75013
		His388	C	2.33072
		Try385	C	2.59490
		Ala202, Gln203	Aps	4.08315
		Ala202	PA	4.63868
A8	− 6.8	Thr206	H	2.29989
		Trp387	H	2.80741
		Gln203	C	2.61251
		His207	C	2.62372
		His386	C	2.27808
		Ala199	X	3.04839
		Ala202, Gln203	Aps	5.04449
		Ala202	PA	5.37466
		Leu391	PA	5.38783
A9	− 6.3	Thr206	H	2.24436
		His207	H	2.85692
		Gln203	C	2.38804
		His388	C	2.74907
		Ala199	X	3.57555
		Trp387	X	3.69043
		Ala202, Gln203	Aps	4.66133
		Ala202	PA	4.75397
A10	− 6.2	Gln203	H	2.42196
		His207	C	2.33298
		His386	C	2.21281
		His388	C	2.59122
		Ala199	X	3.58681
		Ala199	A	4.00484
		Leu390	A	4.28930
		Leu391	A	4.36216
A11	− 6.4	Thr206	H	2.16279
		His207	H	2.85042
		His207	C	2.72972
		His388	C	2.94329
		Ala202, Gln203	Aps	4.61041
		Ala199	A	4.15686
		Leu390	A	4.28001
		Leu391	A	4.38277
		Ala202	PA	4.99532
A12	− 6.8	Gln203	H	2.83201
		Gln203	H	2.89226
		Thr206	H	2.27425
		Gln203	C	2.46807
A13	− 7.0	His386	C	2.55735
		His388	C	2.59835
		His388	C	2.31704
		Ala202, Gln203	Aps	4.45466
		Ala202	PA	5.07784
A14	− 6.8	Thr206	H	2.29165
		His207	H	2.92555
		Gln203	C	2.33844
		His207	C	2.45934
		His386	C	2.57179
		Ala199	X	2.81745
		Ala199	X	2.90187
		Trp387	X	3.00658
		Ala199	A	4.41991
		Leu390	A	4.57220
		Leu391	A	4.43187
A15	− 7.0	Cys41	H	2.46425
		Tyr130	H, X	2.29772
		Tyr130	H, X	2.24943
		His39	H	2.76336
		Val56	C, X	2.33445
		Arg44	X	3.03961
		Gly45	X	3.56243
		Gly45	X	3.19647
		Val46	A	4.45525
		Tyr130	PA	5.33550
		Leu152	PA	5.15844
A16	− 5.8	Ser121	H	2.39860
		Gln373	H	1.79967
		Ile124	H	2.59708
		Ser126	H	2.28029
		Ser121	H	2.41732
		Phe371	C	2.50403
A17	− 6.5	His39	H	2.74091
		His39	H	2.49271
		Cys47	H	2.89928
		Try130	H	2.86112
		Gly135	H	2.45680
		His39	C	2.96484
		Val46	PA	5.46413
		Cys47	PA	4.79158
		Pro153	PA	5.46413
A18	− 6.6	Thr206	H	2.29562
		His207	H	2.91585
		Try385	H	1.88047
		Gln203	C	2.38919
		His207	C	2.47512
		His386	C	2.61248
		Ala199	X	2.89704
		Ala199	X	2.81255
		Trp387	X	3.00480
		Ala199	A	4.42934
		Leu390	A	4.59853
		Leu391	A	4.45042
		His207	PA	4.66626
A19	− 6.7	Trp387	H	2.80137
		Gln203	C	2.62366
		His207	C	2.63009
		His386	C	2.26264
		Ala202, Gln203	Aps	5.02293
		Ala202	PA	5.32595
		Leu391	PA	5.40744
A20	− 6.5	Ala202	H	2.96513
		Gln203	C	2.59609
		His207	C	2.45721
		His386	C	2.43671
		Ala202, Gln203	Aps	5.09370
		Ala202	PA	5.47624
		Leu391	PA	5.40283
A21	− 6.5	Ala202	H	2.40948
		His207	C	2.44292
		His386	C	2.46866
		Ala202, Gln203	Aps	5.09755
		Ala202	PA	5.49241
		Leu391	PA	5.41038

A alkyl, H conventional hydrogen bond, C carbon hydrogen bond, Aps amide-pi stacked, PA Pi-alkyl, Pan Pi-anion, PC Pi-cation, PS Pi-sigma, Ppt Pi-Pi T shaped, X Halogen bond

Molecular orbital analysis

The molecular orbital results are presented in Table 2 and Fig. 2. The chemical reactivity, softness, chemical potential and electron transition from ground state to excited state can be predicted from HOMO, LUMO energy calculation. HOMO–LUMO energy gap works as trigger, where lower energy gaps maximize the chemical reactivity and minimize the kinetic stability and also support the bioactivity of molecules (Azam et al. 2018; Parr and Zhou 1993). In this study, most of the derivatives (except A1, A2, A9 and A18) have lower HOMO–LUMO gap than Asp. The energy gap of Asp is 5.683 eV where A16 shows the lowest energy gap (4.496 eV) as well as the lowest chemical hardness (2.348 eV) with the highest chemical softness (0.426 eV) which may exhibit better chemical reactivity and polarizability.

Table 2.

Energy (eV) of HOMO, LUMO, energy gap, hardness, softness and chemical potential of all optimized structures

Name	HOMO	LUMO	Gap	Hardness	Softness	Chemical potential
Asp	− 7.140	− 1.457	5.683	2.842	0.352	− 4.298
A1	− 9.620	− 2.502	7.118	3.559	0.281	− 6.061
A2	− 7.557	− 1.793	5.764	2.882	0.347	− 4.675
A3	− 6.771	− 1.333	5.438	2.719	0.368	− 4.052
A4	− 6.893	− 1.403	5.490	2.745	0.364	− 4.148
A5	− 6.411	− 1.411	5.000	2.500	0.400	− 3.911
A6	− 6.992	− 1.366	5.556	2.778	0.360	− 4.179
A7	− 6.543	− 1.154	5.389	2.694	0.371	− 3.848
A8	− 7.082	− 1.688	5.394	2.697	0.371	− 4.385
A9	− 7.214	− 1.491	5.723	2.862	0.350	− 4.353
A10	− 6.988	− 1.416	5.572	2.786	0.359	− 4.202
A11	− 6.928	− 1.558	5.370	2.685	0.372	− 4.243
A12	− 6.442	− 1.457	4.985	2.493	0.401	− 3.950
A13	− 6.578	− 1.455	5.123	2.562	0.390	− 4.017
A14	− 7.523	− 1.848	5.675	2.838	0.352	− 4.686
A15	− 7.500	− 1.979	5.521	2.761	0.362	− 4.740
A16	− 5.977	− 1.281	4.696	2.348	0.426	− 3.629
A17	− 6.118	− 0.998	5.120	2.560	0.391	− 3.558
A18	− 7.596	− 1.871	5.725	2.863	0.349	− 4.734
A19	− 6.511	− 1.454	5.057	2.529	0.395	− 3.983
A20	− 6.587	− 1.55	5.037	2.519	0.397	− 4.069
A21	− 7.287	− 1.671	5.616	2.808	0.356	− 4.479

Fig. 2.

Frontier molecular orbital (HOMO and LUMO) and related energy of Asp and A16

Molecular electrostatic potential analysis

Molecular electrostatic potential (MEP) was predicted to forecast possible chemical reactive site, biological recognition and hydrogen bonding interactions of all optimized structures (Scrocco and Tomasi 1973). The negative area is represent with red color which is possible site for electrophilic attack, on the other hand blue color exposed the positive area and possible site for nucleophilic attack (Politzer and Truhlar 2013). From the MEP map (Fig. 3, Fig. S3), area having the negative potentiality over highly electronegative oxygen atoms and positive potentiality over the hydrogen atoms. In this investigation, A14 shows the maximum positive potentiality (+ 0.234 a.u, deep blue), where A12 shows the highest negative potentiality (− 0.229 a.u, deep red) which suggesting maximum possibility for the nucleophilic and electrophilic attack to the respected region.

Fig. 3.

Molecular electrostatic potential (MEP) map of Asp, A12 and A14

Equilibrium geometry analysis

Some selected bond distances and bond angles are tabulated in Table S1 and Table S2 respectively (atom numbers are indicated in the optimized structures). For structural optimization, equilibrium geometry is an essential criterion. Here, calculated data are compared with X-ray diffraction data to observe the significant change after modification (Boczar et al. 2003). There is no significance change observed in the core structure after insertion of different functional group, which supports the geometries of modified structures (Fig.  4).

Fig. 4.

Docked conformation of A(1–2), A4, A(6–14), A16, and A(18–21) at the inhibition binding site of receptor protein 5F1A

Vibration frequency analysis

Selected vibrational frequencies and their spectra are depicted in Table S3 and Fig. S4 respectively. All the vibrational frequencies are calculated in gas phase at the same level of theory and multiplied by the scale factor (0.9627) (Marenich et al. 2009). The infrared (IR) spectra for all compounds were measured in the 0–4000 cm⁻¹ range and helped to indicate regions of absorption due to the respective vibrations. The band found in the region 3052–3117 cm⁻¹ assigned to the aromatic νC–H stretching. The band observed between 1787–1824 cm⁻¹ due to stretching of νC = O (ketone) and another band in the region 1769–1785 cm⁻¹ assigned to symmetric stretching of νC = O (carboxylic) group. The band observed at 3682–3684 cm⁻¹ due to the symmetry stretching of νO–H and band at 3657–3665 cm⁻¹ confirm the stretching of νO–H (carboxylic) group. Vibrational frequencies from 1116–1175 cm⁻¹ has been assign to the νC–O stretching and another band found in between 1261–1282 cm⁻¹ due to the presence of νC–O (carboxylic) stretching. In addition, the peak between 1118–1253 cm⁻¹ and 3587–3697 cm⁻¹ confirming the presence of νC–F and νN–H functional group respectively.

Docking and interactions analysis

Binding affinities and non-bonding interactions are summarized in Table 3. Greater negative values of binding affinity indicate stronger binding between drugs and the receptor protein. Strong hydrogen bonding is the most significant contributing factor in increasing binding affinity of drugs with the receptor. Non-covalent interactions such as hydrogen bond, halogen bond and hydrophobic interaction are involved in the binding of examined structures. Recently, it is reported that, hydrogen bond of < 2.3 Å are able to increase the binding affinity by several magnitude (Wade and Goodford 1989a) and halogen bonds have almost similar importance as hydrogen bond in chemical and biological system (Lu et al. 2012; Sarwar et al. 2013). Due to the addition of new functional groups (–CH₃, –OCH₃, –NH₂, –CH₂NH₂, –NHCOCH₃, –OH, –CH₂OH, –F, –CF₃) not only improved the physicochemical properties but also increased the binding affinity and specialty (Fig. 5).

Fig. 5.

Non-bonding interactions of Asp, A2 and A15 with 5F1A

In this study, the binding affinity of Asp is − 6.5 kcal mol⁻¹, where A2 (− 7.2 kcal mol⁻¹) shows the highest binding affinity and A13 and A15 have the similar binding affinity (− 7.0 kcal mol⁻¹). Some important carbon hydrogen bonds with His207 and His386 residues were observed in Asp, A2, A13 molecules. Pi-alkyl interactions were found almost in all derivatives with the Alanine, Tyrosine, Proline, Leucine, Valine, Histidine and Cysteine residues. Another important interaction, Amide-pi stacked with Ala202, Gln203 residues were found in most of the derivatives. A shorter hydrogen bond (2.3 Å) significantly enhanced the binding property and specialty (Wade and Goodford 1989b). Here, A2 and A15 compounds with improved binding affinities exhibit some important hydrogen bond mediated interactions with Thr206 (2.2889 Å), Cys41 (2.4643 Å), and His39 (2.7634 Å) respectively. Meanwhile, A13 shows some important shorter distance interactions with His388 and His386 mediated by carbon hydrogen bond. In addition, some important hydrogen bonds (≤ 2.3 Å) were observer in A2–A9, A11–A12, A14–A16, and A18 compounds with the Thr206, Gln373, Gln461, Tyr138, and Tyr385 residues. In addition, halogenated compounds showed some important interactions with the following residues; Ala199, Trp387, Tyr130, Try385, His386, Arg44, Val56, and Gly45 mediated by halogen bonds.

ADMET analysis

From ADMET results (Table 4), all the compounds have positive response to blood brain barrier (BBB) and human intestinal absorption. All the derivatives are non-carcinogenic and some of them (A1, A3, A12, A13, A16, A17, A20 and A21) exhibit III category acute oral toxicity where Aspirin shows II category acute oral toxicity. As a result, these derivatives are relatively harmless than parent drug (Asp). Moreover, some of the compounds have higher rat acute toxicity with higher median lethal dose (LD₅₀) values compared to Asp (Walum 1998). All the drugs have weak inhibition to human ether-a-go-go-related gene (hERG) which may lead to long QT syndrome (Sanguinetti and Tristani-Firouzi 2006). All the drugs have no inhibition to P-glycoprotein. Where, inhibition can interrupt the absorption, permeability and retention of the drugs (Amin 2013).

Table 4.

Selected pharmacokinetic parameters of all compounds

Name	Blood brain barrier	Human intestinal absorption	P-glycoprotein inhibitor	hERG	Carcinogen	Rat acute toxicity LD50 (mol/kg)	Acute oral toxicity
Asp	+ (0.938)	+ (0.965)	NI (0.912)	WI (0.943)	NC (0.836)	2.639	II
A1	+ (0. 930)	+ (0.963)	NI (0.982)	WI (0.977)	NC (0.873)	2.037	III
A2	+ (0.981)	+ (0.983)	NI (0.912)	WI (0.978)	NC (0.799)	2.733	II
A3	+ (0.894)	+ (0.978)	NI (0.981)	WI (0.974)	NC (0.856)	2.082	III
A4	+ (0.934)	+ (0.954)	NI (0.906)	WI (0.958)	NC (0.806)	2.740	II
A5	+ (0.884)	+ (0.920)	NI (0.912)	WI (0.958)	NC (0.845)	2.673	II
A6	+ (0.934)	+ (0.954)	NI (0.906)	WI (0.958)	NC (0.806)	2.740	II
A7	+ (0. 884)	+ (0.920)	NI (0.912)	WI (0.958)	NC (0.845)	2.673	II
A8	+ (0.963)	+ (0.969)	NI (0.915)	WI (0.954)	NC (0.800)	2.792	II
A9	+ (0.963)	+ (0.969)	NI (0.915)	WI (0.954)	NC (0.800)	2.792	II
A10	+ (0.962)	+ (0.959)	NI (0.913)	WI (0.966)	NC (0.767)	2.934	II
A11	+ (0.962)	+ (0.959)	NI (0.913)	WI (0.966)	NC (0.767)	2.394	II
A12	+ (0.913)	+ (0.797)	NI (0.971)	WI (0.989)	NC (0.790)	2.318	III
A13	+ (0.841)	+ (0.760)	NI (0.960)	WI (0.986)	NC (0.787)	2.132	III
A14	+ (0.975)	+ (0.990)	NI (0.911)	WI (0.975)	NC (0.771)	2.821	II
A15	+ (0.975)	+ (0.990)	NI (0.911)	WI (0.975)	NC (0.771)	2.821	II
A16	+ (0.588)	+ (0.875)	NI (0.961)	WI (0.969)	NC (0.781)	1.805	III
A17	+ (0.565)	+ (0.850)	NI (0.942)	WI (0.960)	NC (0.787)	1.674	III
A18	+ (0.950)	+ (0.987)	NI (0.898)	WI (0.975)	NC (0.807)	2.895	II
A19	+ (0.829)	+ (0.941)	NI (0.944)	WI (0.952)	NC (0.841)	2.622	II
A20	+ (0.626)	+ (0.898)	NI (0.908)	WI (0.900)	NC (0.863)	1.918	III
A21	+ (0.751)	+ (0.864)	NI (0.809)	WI (0.976)	NC (0.882)	1.970	III

NI non-inhibitor, WI weak-inhibitor, NC non-carcinogenic

Conclusion

In this investigation, Asp and its modified derivatives were studied to explore their physicochemical and prostaglandin inhibition properties. Equilibrium geometry and vibrational frequency calculation supported the modified structures. All the compounds are thermally stable and most of them have lower HOMO–LUMO gape with higher softness values than parent drug. Some of the derivatives have better binding affinity and interactions than the parent drug. Moreover, A2-5F1A complex shows the highest binding affinity than others because of the substitution of hydrogen by CF₃. All the derivatives have improved pharmacokinetic properties and some of them show III category acute oral toxicity which suggesting better oral administration property than Asp. Considering the above investigation, this study can be helpful to design a potential COX-2 inhibitors.

Electronic supplementary material

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Abbreviations

Asp

Aspirin

NSAID

Nonsteroidal anti-inflammation drug

DFT

Density functional theory

HOMO

Highest occupied molecular orbital

LUMO

Lowest unoccupied molecular orbital

MEP

Molecular electrostatic potential

ADMET

Absorption, distribution, metabolism, excretion, toxicity

Author contributions

MU designed the project. TM perform all calculation and data collection. MU and TM wrote the manuscript. All the authors read and approved the manuscript.

Funding

This research not received any fund.

Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest.