Computational studies on the design of NCI natural products as inhibitors to SARS-CoV-2 main protease.

The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 5 million deaths globally. Currently there are no effective drugs available to treat COVID-19. The viral protease replication can be blocked by the inhibition of main protease that is encoded in polyprotein 1a and is therefore a potential protein target for drug discovery. We have carried out virtual screening of NCI natural compounds followed by molecular docking in order to identify hit molecules as probable SARS-CoV-2 main protease inhibitors. The molecular dynamics (MD) simulations of apo form in complex with N3, α-ketoamide and NCI natural products was used to validate the screened compounds. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis revealing dynamical nature of the protein. These findings aid in understanding the binding of natural products and molecular mechanisms of SARS-CoV-2 main protease inhibition.Communicated by Ramaswamy H. Sarma.

Mutational analyses, pharmacophore-based inhibitor design and in silico validation for Zika virus NS3-helicase.

Zika virus is responsible for causing Zika infections and was declared as a public health emergency of international concern in February 2016. The Zika virus NS3-helicase is a viable drug target for the design of inhibitors due to its essential role in the replication of viral genome. The viral RNA is unwound by the NS3-helicase in order to enable the reproduction of viral genome by the NS5 protein. Zika virus infections in humans are being reported for the last 15 years. We have therefore carried out amino acid mutational analyses of NS3-helicase. NS3-helicase has two crucial binding sites: the ATP and RNA binding sites. The cofactor-ATP based pharmacophore was generated for virtual screening of ZINC database using Pharmit server, that is followed by molecular docking and molecular dynamics simulations of potential hits as probable Zika virus NS3-helicase inhibitors at the cofactor binding site. The drug-like properties of the molecules were analysed and, DFT calculations were performed on the five best molecules to reveal their stability in solvent phase compared to gas phase, the HOMO and LUMO and electrostatic potential maps to analyze the electronic and geometric characteristics. These are significant findings towards the discovery of new inhibitors of Zika virus NS3-helicase, a promising drug target to treat the Zika virus infection.Communicated by Ramaswamy H. Sarma.

Molecular mechanism of ATP and RNA binding to Zika virus NS3 helicase and identification of repurposed drugs using molecular dynamics simulations.

Congenital Zika virus syndrome has caused a public health emergency of international concern. So far, there are no drugs available to prevent or treat the infection caused by Zika virus. The Zika virus NS3 helicase is a potential protein target for drug discovery due to its vital role in viral genome replication. NS3 helicase unwinds the viral RNA to enable the reproduction of the viral genome by the NS5 protein. NS3 helicase has two crucial binding sites; the ATP binding site and the RNA binding site. We used molecular docking and molecular dynamics (MD) simulations to study the structural behavior of Zika virus NS3 helicase in its apo form and in the presence of ATP, single-stranded RNA, and both ATP-RNA to understand their potential implications in NS3 helicase activity. Further, we have carried out virtual screening of FDA approved drugs, followed by molecular docking to identify the ATP-competitive hit molecules as probable Zika virus NS3 helicase inhibitors. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis that reveals fluctuations in the R-loop. These findings aid in understanding the molecular mechanisms of the simultaneous binding of ATP and RNA, and guide the design and discovery of new inhibitors of the Zika virus NS3 helicase as a promising drug target to treat the Zika virus infection. Communicated by Ramaswamy H. Sarma.

Multiple e-pharmacophore modelling pooled with high-throughput virtual screening, docking and molecular dynamics simulations to discover potential inhibitors of Plasmodium falciparum lactate dehydrogenase (PfLDH).

Development of new antimalarial drugs continues to be of huge importance because of the resistance of malarial parasite towards currently used drugs. Due to the reliance of parasite on glycolysis for energy generation, glycolytic enzymes have played important role as potential targets for the development of new drugs. Plasmodium falciparum lactate dehydrogenase (PfLDH) is a key enzyme for energy generation of malarial parasites and is considered to be a potential antimalarial target. Presently, there are nearly 15 crystal structures bound with inhibitors and substrate that are available in the protein data bank (PDB). In the present work, we attempted to consider multiple crystal structures with bound inhibitors showing affinity in the range of 1.4 × 102-1.3 × 106 nM efficacy and optimized the pharmacophore based on the energy involved in binding termed as e-pharmacophore mapping. A high throughput virtual screening (HTVS) combined with molecular docking, ADME predictions and molecular dynamics simulation led to the identification of 20 potential compounds which could be further developed as novel inhibitors for PfLDH.