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COMPUTER AIDED DRUG DESIGN APPROACH FOR DENGUE VIRUS TYPE 2 NS2B/NS3 PROTEASE INHIBITORS

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Dengue is a mosquito-borne viral disease that has rapidly spread in all regions of WHO in recent years and transmitted by female mosquitoes mainly by species Aedes aegypti and, to a lesser extent, Ae. albopictus. Dengue virus has 5 distinct serotypes (based on antigenicity): DENV-1, DENV-2, DENV-3, DENV-4 and DENV-5. The most prominent being DENV-2: especially in Asian region. This virus consists of three structural proteins (capsid, pre-membrane and envelope) and seven non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5. The first dengue vaccine, Dengvaxia® was not effective, so need of reliable drug. DENV-2 NS2B/NS3 protease is the most common target in the drug design of dengue disease where NS3 acts as the protease and NS2B as a cofactor. The purpose of this study is to design the Dengue virus type 2 NS2B/NS3 protease inhibitors using computer aided drug design approach. This research focuses on homology modelling, molecular dynamics simulations, virtual screening and molecular docking of ZINC database compounds against Dengue Virus (DENV) type 2 full length NS2B/NS3 protease (homology model). Target protein sequences (NS2B and NS3 of Dengue virus type 2) were searched in UniProt (accession no. P29990). Homology modelling of NS2B/NS3 protease was done using SWISS-MODEL taking template 5yvj.1 obtained from the SMTL. Model built (model_01.pdb) was viewed by PyMOL. The model built was further used for molecular dynamic simulation using YASARA server. The minimized model then used for binding pocket detection using fconv and CASTp and performed virtual screening of potential inhibitors from ZINC database. Top 5 ligands were then taken and energy minimization was done. After that, molecular docking was done using AutoDock Vina and analysis was done using PyMoL. As an outcome of the research, five compounds from ZINC database (ZINC IDs: ZINC000103760984, ZINC000051951669, ZINC000051951668, ZINC000150664074, and ZINC000095539256) have shown strong bindings as compared to reference ligand Panduratin A. This research also explores that these compounds can be utilized as potential drug candidates against DENV NS2B/NS3 protease on the basis of drug profiling (insilico ADMET assay).

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