Remdesivir (GS-5734) as a therapeutic option of 2019-nCOV main protease – in silico approach

Abstract

2019-Novel Coronavirus (2019-nCOV), enclosed large genome positive-sense RNA virus characterized by crown-like spikes that protrude from their surface, and have a distinctive replication strategy. The 2019-nCOV belongs to the Coronaviridae family, principally consists of virulent pathogens showing zoonotic property, has emerged as a pandemic outbreak with high mortality and high morbidity rate around the globe and no therapeutic vaccine or drugs against 2019-nCoV are discovered till now. In this study, in silico methods and algorithms were used for sequence, structure analysis and molecular docking on M pro of 2019-nCOV. The co-crystal structure of 2019-nCOV protease, 6LU7 have $99% identity with SARS-CoV protease. The 6LU7 residues, Cys145 and His164 are playing a significant role in replication and are essential for the survival of 2019-nCOV. Alongside, 2019-nCOV M pro sequence is non-homologous to human host-pathogen. Complete genome sequence analysis, structural and molecular docking results revealed that Remdesivir is having a better binding affinity with-8.2 kcal/ mol than the rest of protease inhibitors, and peptide. Remdesivir is strongly forming h-bonds with crucial M pro residues, Cys145, and His164. Further, MD simulation analysis also confirmed, that these residues are forming H-bond with Remdesivir during 100 ns simulations run and found stable ($99%) by RMSD and RMSF. Thus, present in silico study at molecular approaches suggest that, Remdesivir is a potent therapeutic inhibitor against 2019-nCoV.

New Concept of Small Molecules Interaction with Proteins – An Application to Potential COVID-19 Drugs

“…Remdesivir inhibits production of viral RNA and the mechanism how it is happening is not yet well explained. Some of its metabolites are interfering with viral RNAdependent RNA polymerase, while remdesivir can interact with viral protease [32], which interaction we have analyzed here. Activity of retroviral proteases is one of the critical steps in viral replication as this enzyme cleaves newly synthetized viral poly proteins to create mature protein components of an infectious virion.…”

In silico exploration of novel protease inhibitors against coronavirus 2019 (COVID-19)

“…It is clearly showed that the majority of interactions are electrostatic and colored in violet. Remdesivir interacts with the viral RNA-dependent RNA polymerase, but some articles stated that remdesivir is a protease inhibitor [ 46 , 47 ], so we decided to dock remdesivir into the main protease. The resulting CDOCKER energy and GOLD score value of remdesivir is very low, demonstrates that remdesivir is not a protease inhibitor.…”

Exploring the effectiveness of SARS-CoV-2 3CLpro inhibitors through molecular dynamics and binding free energy simulations

“…Additionally, the docking and molecular dynamics were performed for ligands such as Hydroxychloroquine, Chloroquine [15,16], Remdesivir [17][18][19], N3 [20] and 11b [21], to serve as an energy parameter to assess the a nity of the other ligands -positive control. The structure of the ligands with possible 3CLpro inhibitory activities, derived from the Virtual Screening carried out by HOFMARCHER [14] were obtained from the ZINC database (https://zinc.docking.org/).…”

“…In December 2019 in Wuhan city in China, local doctors identi ed a new coronavirus as the causative agent of a severe acute respiratory syndrome type [1] later called Coronavirus Disease 2019 (COVID- 19). COVID-19 is a disease caused by SARS-CoV-2 [2], SARS are commonly characterized by high fever, malaise and non-productive cough and in some severe cases can cause generalized interstitial in ltration of the lungs, leading to the cases of intubation and mechanical ventilation of those affected [3].…”