ABSTRACT
Triticum aestivum is an important crop worldwide, which is a large source of food grain. T.aestivum demands on developed countries will grow every year, this increase in the demand is profoundly serious especially in the light climate change which would lead to a 29% reduction in final productivity. Rust fungus attacks the T.aestivum, specifically newly planted T.aestivum plants, which block the vascular system, stun, and finally damage grain and tillers. In present study we predict the 3D structure then find the binding pocket and conserved domains for MAPkinase-1 of Puccinia triticina. After that, screen the FungiPAD, PubChem, NPAtlas databases by physicochemical properties, docking, clustering, ADME (Absorption, distribution, metabolism, and excretion) and PAINS (pan assay interference compounds) filter analysis. Through this screening process screen the nine compounds, which are benzovindiflupyr, furametpyr, isopyrazam, fenaminstrobin, and flumorph from Fungicide database: zoxamide, vinclozolin, pentachloronitrobenzene, and dithianon from PubChem database, based on the binding energy, clustering, ADME and PAINS analysis. All these nine compounds bind in the same pocket and show the same pattern of interaction. Among these nine compounds, select the two compounds (PubChem:122087 (-6.96 kcal/mol) and FDBD02904 (-8.62 kcal/mol)) based on binding energy for 100 ns MD simulation and free energy calculation. MD simulation shows stability throughout the simulation, and it shows the sable interaction when compounds bind to the MAPKinase 1 protein which may help to protein kinase pathways in plant defense response. This result helps to design alternative fungicide against the wheat rust disease.Communicated by Ramaswamy H. Sarma.
ABSTRACT
A new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a respiratory infection out broke in December 2019 in Wuhan, Hubei province, China, resulted in pandemic conditions worldwide. COVID-19 spread swiftly around the world over with an alert of an emergency for an adequate drug. Therefore, in this research, we repurposed the FDA-approved medicines to find the prominent drug used to cure the COVID infected patients. We performed homology modeling of the transmembrane serine protease 2 (TMPRSS2), responsible for the viral entry. The prediction of the transmembrane region and the Conserved Domain in TMPRSS2 protein was made for docking. 4182 FDA-approved compounds from the ZINC database were downloaded and used for the calculation of physicochemical properties. Two thousand eight hundred fifteen screened compounds were used for molecular docking against the modelled protein structure. From which top hit compounds based on binding energy were extracted. At 1st site pose, ZINC3830554 showed the highest binding energy -12.91kcal/mol by forming Salt Bridge at LYS143, Hydrogen bond at ALA8, VAL45, HIS47, SER142, ASN277, ASN359, and TRP363. The hydrophobic Interactions at PHE3, LEU4, ALA7, ALA8, ALA139, PRO197, and PHE266. In the 2nd site pose, ZINC203686879 shows the highest binding energy (-12.56 kcal/mol) and forms a hydrophobic interaction with VAL187, VAL189, HIS205, LYS301, GLN347, TRP370 and hydrogen bond was at GLY300, THR302, GLN347, SER350 residues. These hit compounds were subjected to stability checks between the protein-ligand complex through the dynamics simulation (MD), and binding free energy was calculated through the Molecular Mechanics energies combined with Poisson-Boltzmann (MM/PBSA) method. We hope that hit compounds would be an efficient inhibitor that can block the TMPRSS2 activity and resist the entry of the SARS-CoV-2 virus into targeted human cells by reducing the virus's infectivity and transmissibility.
