Repurposing drugs and identification of inhibitors of integral proteins (spike protein and main protease) of SARS-CoV-2

Abstract

The outbreak of Coronavirus infection (COVID-19) has prompted the World Health Organisation (WHO) to declare the outbreak, a Public Health Emergency of International concern. As part of the efforts to discover lead compounds for clinical use, 53 molecules were screened using molecular docking and dynamic simulations (MDS) techniques to identify potential inhibitors of SARS-CoV-2 spike protein (COVID-19 S gp ) and main protease (COVID-19 M pro ) or both. Lopinavir (LPV), nelfinavir (NEF), hydroxychloroquine (HCQ), remdesivir (RDV) and an irreversible inhibitor of SARS-CoV (N3) were used as standard drugs for COVID-19 M pro , while zafirlukast (ZFK) and cefoperazone (CSP)) as standard drugs for COVID-19 S gp . After 100 ns of MDS, with reference to standard drugs (N3, −52.463 Kcal/mol, NEF, −51.618 Kcal/mol, RDV, −48.780 Kcal/mol, LPV, −46.788 Kcal/mol, DRV, −33.655 Kcal/mol and HCQ, −21.065 Kcal/mol), five molecules, HCR, GRN, C3G, EGCG, and K7G were predicted to be promising inhibitors of COVID-19 M pro with binding energies of −53.877 kcal/mol, −50.653 Kcal/mol, −48.600 kcal/mol, −47.798 kcal/mol and −46.902 kcal/mol, respectively. These lead molecules were then docked at receptor-binding domain (RBD) of COVID-19 S gp to examine their inhibitory effects. C3G, GRN and K7G exhibited higher binding energies of −42.310 kcal/mol, −32.210 kcal/mol, −26.922 kcal/mol than the recorded values for the reference drugs (CSP, −35.509 kcal/mol, ZFK, −24.242 kcal/mol), respectively. The results of the binding energy and structural analyses from this study revealed that C3G, GRN and K7G could serve as potential dual inhibitors of COVID-19 S gp and COVID-19 M pro , while HCR and EGCG would be inhibitors of COVID-19 Mpro. Communicated by Ramaswamy H. Sarma

Phenolics Profiling of Carpobrotus edulis (L.) N.E.Br. and Insights into Molecular Dynamics of Their Significance in Type 2 Diabetes Therapy and Its Retinopathy Complication

“…Additionally, better poses were observed for epicatechin, luteolin-7- O -beta- d -glucoside, isorhamnetin-3- O -rutinoside, rutin, hyperoside and procyanidin with alpha-amylase compared to the resulting complexes with acarbose ( Table 3 ). While most of the identified compounds including 1,3-dicaffeoxyl quanic acid, chlorogenic acid, epicatechin, isorhamnetin-3- O -rutinoside, luteolin-7- O -beta- d -glucoside, myrcetin, rutin, cacticin, hyperoside and procyanidin showed good docking with alpha-glucosidase as depicted by the higher negative values than acarbose, other compounds (epicatechin, isorhamnetin-3- O -rutinoside, chlorogenic acid and rutin) had commendable binding at the active sites of the three enzymes ( Table 3 ), which is indicative of their prospective interaction with the enzymes [ 28 ]. However, since docking is only a preliminary reflection of the ligand’s fitness within the binding pocket of a receptor, the binding orientations of the studied phenolics were subjected to further binding energy calculations and MDS.…”

“…The nature/extent of stability and convergence of a ligand-receptor system is normally measured by RMSD [ 28 ]. In this study, the average RMSD values for procyanidin, rutin and acarbose (standard drug) were 1.62 Å, 1.68 Å and 1.82 Å, respectively, while it was 2.04 Å for α-amylase (apo-enzyme) ( Figure 2 A).…”

“…Radius of gyration (RoG) determines the total compactness of the enzyme-inhibitor binding [ 28 , 32 ]. It is a measure of densification of the protease structure [ 33 ], and the smaller the RoG value, the better the protease stability.…”

“…The binding property of the inhibitor or ligand and the active site residues of each protein was further evaluated by RMSF. Increased or decreased fluctuations are sin qua non to high or low flexibility movement or interaction between ligands and the receptor amino acids residues [ 28 ]. In the finding for alpha-amylase system, rutin (2.79 Å) followed by acarbose (2.54 Å) exhibited the highest average RMSF values, while the lowest value was found with procyanidin (2.05 Å) among the studied interactions.…”

“…The MDS was achieved as recently reported [ 28 ], using the GPU (force fields) version obtainable in AMBER package, where the description of the system by FF18SB variant of the AMBER force field was carried out [ 42 ]. With the aid of Restrained Electrostatic Potential (RESP) and the General Amber Force Field (GAFF) methods of the ANTECHAMBER assisted with information on atomic partial charges for the compounds.…”