Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study

Abstract

In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinderV R library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski's rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC-ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-M pro was found to have minimum binding energy of À10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of À8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of À63.47 ± 3 and À63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19.

Probing the Action of Screened Anticancer Triazole–Tetrazole Derivatives Against COVID-19 Using Molecular Docking and DFT Investigations

“…The achieved docking scores are noteworthy compared to previously tested drugs, with the 1, 2, 3-triazole derivatives used in this study having binding affinities predicted to be between −6.0 and −8.8 kcal/mol ligand. 40,41 The least binding energy (−8.97 Kcal/mol) of TD3 qualifies it as a potent inhibitor of SARS-CoV-2 M pro . TD1, TD3, and TD4 have only one hydrogen bond interaction with residues HIS41, GLU166, and THR26, respectively.…”

Synthesis, Anticancer and Antibacterial Activity of Mannose-based bis-1,2,3-Triazole Derivatives

“…1 H NMR (600 MHz, CDCl3) δ ppm: 5.37 (s, 1 H, H-1), 4.80 (dd, J = 5.8 Hz, J = 3.6 Hz, 1 H, H-3), 4.61 (d, J = 5.9 Hz, 1 H, H-2), 4.41-4.37 (m, 1 H, H-5), 4.18 (dd, J = 7.1 Hz, J = 3.7 Hz, 1 H, H-4), 4.08 (dd, J = 8.6 Hz, J = 6.3 Hz, 1 H, Ha-6), 4.04 (dd, J = 8.6 Hz, J = 4.7 Hz, 1 H, Hb-6), 1.46 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 1.37 (s, 3 H, CH3), 1.32 (s, 3 H, CH3). 13 38 2,3:5,6-Di-O-isopropylidene--Dmannofuranose (6) (5 g, 18.5 mmol) was added to MeOH (25 mL) and the mixture was stirred for a while until diacetonide 2 was fully dissolved. Potassium carbonate (16 g, 115.7 mmol) was added and the mixture was stirred at 80 °C in an oil bath to give a milky suspension.…”

Implication of in silico studies in the search for novel inhibitors against SARS‐CoV‐2

“…carried out in silico studies on Mpro inhibitors from 1,2,3-triazolephthalimide derivatives, where the seven best compounds were subjected to a MD study; among them, one compound 43) showed a promising docking result, with a binding energy of −10.26 kcal/mol, as compared to the binding energy of −7.0 kcal/mol of the N3 ligand. [55] better stability and binding affinity to the target protein; hence, it could act as a possible Mpro inhibitor. [56] Kumar et al screened several metabolites obtained from natural sources, and their in silico study was carried out using MD and MDS; they found that ursolic acid (45), carvacrol (46) and oleanolic acid (47) showed binding energies of −4.0, −0.0 and −5.9 kcal/mol, respectively.…”

“…[58] Ibrahim et al screened 18 anti-COVID-19 drug candidates and performed an in silico study; they found that compound (3R,3aS,6aR)- (54) showed good binding energy and good stability tested by a MDS. [59] Choudhury investigated the active phytoconstituents of the Indian medicinal herb T. cordifolia (Giloy) against the Mpro protein, where (Figure 11) berberine (55) showed better binding affinity with (−7.3 kcal/mol). [60] Rout et al…”