Screening and analysis of bioactive food compounds for modulating the CDK2 protein for cell cycle arrest: Multi-cheminformatics approaches for anticancer therapeutics

摘要

The cyclin-dependent kinase-2 (CDK2) belongs to the protein kinase family and its overexpression leads to an unusual regulation of cell-cycle which directly linked with hyperproliferation in many cancer cell types. CDK2 activation spontaneously promotes the cell cycle progression and also involved in a large number of cellular processes including cell cycle regulation, DNA replication, DNA damage response and apoptotic pathways, therefore targeting the CDK2 can be reemerged as a therapeutic boulevard to restrain cancer cell proliferation. For the last two decades, emerging evidences suggested that CDK2 inhibition draws out some antitumor/anticancer activity, which has driven the research possibility for developing next-generation newer or cost-effective inhibitors with greater speci ficity to CDK2. In the current work, compounds from the FooDB-a world 's largest food constituents database was retrieved and curated and followed by multi-pharmacoinformatics approaches adopted to find out potential CDK2 inhibitors. The curated dataset was considered for screening through "Virtual Screening Work flow" (VSW) employed in Schro Eurodinger suite. The numbers of cost-effective food constituents were reduced by removing low potential molecules in terms of interaction af finity and further explored for pharmaco-kinetics analysis. Based on strong binding interaction pro files with the lowest binding interactions af-finity and energy values, four food compounds were proposed as CDK2 inhibitors. A number of key analyzing parameters from molecular dynamics (MD) simulations studies were successfully substanti-ated that all four proposed food compounds can act as CDK2 inhibitors based on their pro ficient structural and molecular interactions integrity with CDK2 protein following in the active site cavity. Furthermore, the binding free energy was calculated using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach from the entire trajectory frames derived in MD simulation revealed strong interaction af finity. The binding free energy was found to be in the range of -991.831 to -210.452 kJ/mol. High binding free energy was undoubtedly explained that all molecules possess strong affection towards CDK2. Hence, proposed molecules may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation. (C) 2020 Elsevier B.V. All rights reserved.