Docking and simulation studies on cyclin D/CDK4 complex for targeting cell cycle arrest in cancer using flavanone and its congener

Abstract

Flavanone compounds are naturally occurring phytochemicals present in most of citrus fruits reported to be a potential anticancer moiety as it majorly participates in the inhibition of the cell cycle, apoptosis, and angiogenesis. Because of poor bioavailability, natural flavanones were not used as therapeutic targets so flavanone congeners were prepared by modifying at B-functional group using compound libraries such as PubChem Database. Cyclin-dependent kinase is primarily activating the cell cycle and potentiating the M phase, in order to control the cell cycle in cancer cyclin-dependent pathway was targeted and potential cyclin D/CDK4 receptor protein was retrieved from Protein Data Bank (PDBID:2W9Z). The binding site was determined using FlexX docking. Flavanone and its congeners were docked against the 2W9Z receptor protein with the docking software FlexX. For validation of docking results, molecular dynamics simulations of the best-fitting molecule were carried out using Desmond Package. Noncovalent interactions like hydrogen bonds, electrostatic interaction, and Van der walls potentials for stable conformations were calculated. Thus, upon docking and molecular dynamics studies, we discovered the potential flavanone derivatives such as Flavanone 20, Flavanone 25, and Flavanone 29, will become a potential drug target in controlling cell cycle arrest and may become a futuristic candidate in targeting cancer.

Keywords: Cancer; CyclinD/CDK4; Flavanones; Molecular docking; Molecular dynamics simulations.