Computational Evaluation of the Inhibition Efficacies of HIV Antivirals on SARS-CoV-2 (COVID-19) Protease and Identification of 3D Pharmacophore and Hit Compounds

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus behind the fast-spreading coronavirus disease 2019 (COVID-19). Pharmaceutical researchers are currently researching medications or preventive vaccines that may be used to treat and combat the spread of COVID-19. Health practitioners all over the world are treating patients with currently available antiviral drugs, primarily the protease inhibitors used for HIV treatment. The present study mainly aims to evaluate the potencies of eight anti-HIV drugs to inhibit coronavirus protease using in silico methods. Derivation of pharmacophore, identification of hit molecules, and checking their virtual inhibition efficacies on the COVID-19 protease were also carried out in the present investigation. Classification of eight drug molecules (atazanavir, darunavir, fosamprenavir (amprenavir—metabolised product), saquinavir, lopinavir, ritonavir, nelfinavir, and indinavir) based on their molecular structures was completed and reported. The X-ray crystallographic structure of the main protease of coronavirus (SARS-CoV-2 protease) was obtained from the Protein Data Bank and prepared for computational studies using Edu PyMOL software. Docking studies were performed with AutoDock Vina software, and the results were evaluated with Discovery Studio software. The binding scores of the drugs on protease followed the order saquinavir > nelfinavir > lopinavir = indinavir > darunavir > amprenavir > ritonavir > atazanavir. Web servers such as PharmaGist and ZINCPharmer were employed to derive the 3D pharmacophore and to identify potential hit compounds, respectively. The identified hit molecules were docked with the SARS-CoV-2 protease and analysed. A detailed account of the type of interaction between the protease and the molecules is discussed. The majority of hit compounds displayed appreciable binding affinities on coronavirus protease. Three hit compounds possess structures similar to that of natural products, viz., flavonoids, and nucleoside. These molecules were hydrophilic and slightly deviated from Lipinski parameters. All other derived molecules obeyed the Lipinski rule. In vitro, in vivo, and toxicological studies of these compounds have to be performed before checking the actual druggability of these compounds.

Discovery of Novel Coumarin Derivatives as Potential Dual Inhibitors against α-Glucosidase and α-Amylase for the Management of Post-Prandial Hyperglycemia via Molecular Modelling Approaches

“…The PharmaGist webserver was used to generate a ligand-based 3D pharmacophore based on the refined binding pose of HIT1 from MD simulations to discover pharmacophoric features by coumarin-like derivates and new molecular scaffolds for the dual inhibition of the drug targets of interest [25]. Among the several outcomes obtained, appropriate pharmacophoric features were chosen from the webserver independently that might lead to the inhibition of the respective drug targets of interest, α-glucosidase and α-amylase.…”

Ligand-based quantitative structural assessments of SARS-CoV-2 3CLpro inhibitors: An analysis in light of structure-based multi-molecular modeling evidences

“…Several FDA-approved drugs and other compounds which have already been repurposed by several groups of researchers [ 3 , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] , [76] ] were considered here to judge whether our QSAR models can explain/predict these molecules or not.…”

“…The 3 rd highest active compound saquinavir was studied through molecular docking analysis by different groups of researchers [ 58 , 63 , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] , [94] ]. Hall et al [86] reported a docking score of -7.285 kcal/mol while binding to the SARS-CoV-2 3CL pro (PDB: 6LU7).…”

“…Saquinavir also showed similar binding energy (-9.6 kcal/mol) while binding to SARS-CoV-2 3CL pro (PDB: 6LU7) that was noticed by the molecular docking study conducted by Ortega et al [88] . Raphael et al [58] examined that saquinavir had binding energy of -9.0 kcal/mol with SARS-CoV-2 3CL pro (PDB: 6LU7) making several hydrogen bonding interactions with Glu166, His41, His164, Gln189 along with several π-alkyl interactions.…”

Structure-Function Characteristics of SARS-CoV-2 Proteases and Their Potential Inhibitors from Microbial Sources

“…These compounds are the FDA-approved drugs of HIV. Similarly, Raphael and Shanmughan [140] also examined the HIV-protease inhibitors of atazanavir, darunavir, fosamprenavir, saquinavir, lopinavir, ritonavir, nelfinavir, and indinavir against 3CLpro-CoV2. The result showed that the binding energy ranged from −6.4 to −9.0 kcal/mol.…”