Identification of Novel Lead Molecules against Hexokinase-2 using Structure-based Virtual Screening, Molecular Docking and Molecular Dynamics Simulations
TL;DR
This study considered HK2 as a promising target for anticancer strategies by screening a large in-house library of 1.28 million compounds and obtained several lead molecules that exhibited favourable XPG and MM/GBSA scores, steady binding trajectories and sustained interactions.
Abstract
Cancer cells show accelerated glucose metabolism, a significant hallmark, supporting their growth and survival. The first rate-limiting step of glycolysis is catalyzed by an enzyme Hexokinase-2 (HK2) and is commonly overexpressed in many cancers compared to normal cells. Our previous microarray and validation by qPCR showed overexpression of HK2 in transformed fibroblast cells, generated by cellmediated adhesion, as well as in the generated tumors. An epigenetic modification in the promoter region of HK2 and its release into the bloodstream was also observed in the clinical samples of cancer (unpublished data). Because of its strong association with cancer progression and tissue-specific expression, the present study considered HK2 as a promising target for anticancer strategies. A structure-based virtual screening procedure and 300ns MD simulations were used to identify potential lead molecules to inhibit HK2 activity in cancer cells by screening a large in-house library of 1.28 million compounds. Identified lead molecules were evaluated based on XPG docking score, MM/GBSA analysis, ADMET and MD simulations across the selected three HK2 co-crystal structures with open and closed conformation states. Among the several lead molecules obtained, lead 1 of each target exhibited favourable XPG and MM/GBSA scores, steady binding trajectories and sustained interactions.