ABSTRACT
SARS-CoV-2, a new coronavirus emerged in 2019, causing a global healthcare epidemic. Although a variety of drug targets have been identified as potential antiviral therapies, and effective candidate against SARS-CoV-2 remains elusive. One of the most promising targets for combating COVID-19 is SARS-CoV-2 Main protease (Mpro, a protein responsible for viral replication. In this work, an in-house curated library was thoroughly evaluated for druggability against Mpro. We identified four ligands (FG, Q5, P5, and PJ4) as potential inhibitors based on docking scores, predicted binding energies (MMGBSA), in silico ADME, and RMSD trajectory analysis. Among the selected ligands, FG, a natural product from Andrographis nallamalayana, exhibited the highest binding energy of -10.31 kcal/mol close to the docking score of clinical candidates Boceprevir and GC376. Other ligands (P5, natural product from cardiospermum halicacabum and two synthetic molecules Q5 and PJ4) have shown comparable docking scores ranging -7.65 kcal/mol to -7.18 kcal/mol. Interestingly, we found all four top ligands had Pi bond interaction with the main amino acid residues HIS41 and CYS145 (catalytic dyad), H-bonding interactions with GLU166, ARG188, and GLN189, and hydrophobic interactions with MET49 and MET165 in the binding site of Mpro. According to the ADME analysis, Q5 and P5 are within the acceptable range of drug likeliness, compared to FG and PJ4. The interaction stability of the lead molecules with viral protease was verified using replicated MD simulations. Thus, the present study opens up the opportunity of developing drug candidates targeting SARS-CoV-2 main protease (Mpro) to mitigate the disease.
ABSTRACT
The novel coronavirus 2 (nCoV2) outbreaks took place in December 2019 in Wuhan City, Hubei Province, China. It continued to spread worldwide in an unprecedented manner, bringing the whole world to a lockdown and causing severe loss of life and economic stability. The coronavirus disease 2019 (COVID-19) pandemic has also affected India, infecting more than 10 million till 31st December 2020 and resulting in more than a hundred thousand deaths. In the absence of an effective vaccine, it is imperative to understand the phenotypic outcome of the genetic variants and subsequently the mode of action of its proteins with respect to human proteins and other bio-molecules. Availability of a large number of genomic and mutational data extracted from the nCoV2 virus infecting Indian patients in a public repository provided an opportunity to understand and analyze the specific variations of the virus in India and their impact in broader perspectives. Non-structural proteins (NSPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus play a major role in its survival as well as virulence power. Here, we provide a detailed overview of the SARS-CoV2 NSPs including primary and secondary structural information, mutational frequency of the Indian and Wuhan variants, phylogenetic profiles, three-dimensional (3D) structural perspectives using homology modeling and molecular dynamics analyses for wild-type and selected variants, host-interactome analysis and viral-host protein complexes, and in silico drug screening with known antivirals and other drugs against the SARS-CoV2 NSPs isolated from the variants found within Indian patients across various regions of the country. All this information is categorized in the form of a database named, Database of NSPs of India specific Novel Coronavirus (DbNSP InC), which is freely available at http://www.hpppi.iicb.res.in/covid19/index.php.