Potential inhibitors of SARS-cov-2 RNA dependent RNA polymerase protein: molecular docking, molecular dynamics simulations and MM-PBSA analyses

Abstract

The SARS-cov-2 RNA dependent RNA polymerase (nsp12) is a crucial viral enzyme that catalyzes the replication of RNA from RNA templates. The fixation of some ligands in the active site may alter the viral life cycle. The aim of the present study is to identify the conservation level of nsp12 motifs (A-G), using consurf server, and discover their interactions with rifabutin, rifampicin, rifapentin, sorangicin A, streptolydigin, myxopyronin B, VXR and VRX using AutoDockTools-1.5.6, Gromacs 2018.2 and gmmpbsa. Thus, the most of amino acids residues located in nsp12 protein Motifs (A-G) were predicted as highly conserved. The binding energies of streptolydigin, VXR, rifabutin, rifapentine, VRX, sorangicin A, myxopyronin B and rifampicin with nsp12 protein are À8.11, À8.23, À7.14, À6.94, À6.55, À5.46, À5.33 and À5.26 kcal/mol, respectively. In the other hand, the binding energies of ligand in the same order with nsp7-nsp8-nsp12 complex are À7.23, À7.08, À7.21, À7, À6.59, À8.73, À5.52, À5.87 kcal/ mol, respectively. All ligands interact with at least two nsp12 motifs. The molecular dynamics simulation of nsp12-streptolydigin and nsp12-VXR complexes shows that these two complexes are stable and the number of hydrogen bonds as a function of time, after 30 ns of simulation, varies between 0 and 6 for nsp12-streptolydigin complex and between 0 and 4 for nsp12-VXR complex. The average of free binding energies obtained using g_mmpbsa, after 30 ns of simulation, is À191.982 Kj/mol for nsp12-streptolydigin complex and À153.583 Kj/mol for nsp12-VXR complex. Our results suggest that these ligands may be used as inhibitors of SARS-cov-2 nsp12 protein.

An in-silico study on selected organosulfur compounds as potential drugs for SARS-CoV-2 infection via binding multiple drug targets

“…No. Compound name Binding energy (kcal/mol) against SARS-CoV-2 proteins Mpro [24] (6Y84) PLpro [25] (6W9C) Spro [26] (6LZG) RdRp [27] (6M71) Helicase * [28] (6JYT/6ZSL) 1 Metacycline -9.1 2 Dutasteride -8.9 -9.9 # 3 Dihydroergotamine -8.6 -9.3 # 4 Nelfinavir -8.6 5 Tetracycline -8.1 6 Cryptophycin 1 -7.7 7 Cryptophycin 52 -8.3 ** -7.6 8 Deoxycylindrospermopsin -8.6 ** -7.9 9 Famotidine -6.0 ## -7.9 -6.8 ## -5.9 ## 10 Tegobuvir -8.1 11 Bromocriptin -7.7 12 Baicalin -7.6 13 Deleobuvir -7.6 14 Dantrolene -7.6 ...…”

Rifampicin for COVID-19

“…A recent study found the highly conserved nsp12 motifs (A-G), and discovered the interactions with rifabutin and rifampicin, among other ligands. Both of them interacted with at least two nsp12 motifs, indicating that they could be both used as inhibitors of SARS-CoV-2 nsp12 protein[ 44 ]. Another in silico docking approach also found that rifampicin has good binding affinity with the COVID-19 protease[ 45 ], proposing its use as therapeutic treatment as well as prophylaxis.…”

Structural insights into conformational stability of ESR1 and structure base screening of new potent inhibitor for the treatment of Breast Cancer

“…Otherenergies (polar and non-polar solvation) were predicted in respective steps. Herein, the non-polar solvation energy was generated using the solvent-accessible surface area (SASA) model [141][142][143][144][145][146][147][148].…”