Scientific African (Mar 2022)
Exploring the inhibitory mechanism of resorcinylic isoxazole amine NVP-AUY922 towards the discovery of potential heat shock protein 90 (Hsp90) inhibitors
Abstract
Heat shock protein 90 (Hsp90) is an ATP-dependant molecular chaperone that facilitates protein maturation while protecting cancer cells from temperature-induced stress. Hsp90, therefore, remains an attractive target for anticancer drug development. The study aimed to use multidimensional computational drug design to discover new hit compounds that potentially interact with the ATP pocket of Hsp90 and can be used as effective anticancer drugs. An in-house pharmacophore-based virtual screening (PBVS) protocol was used to identify potential Hsp90 inhibitors. Molecular docking, screening, and molecular dynamics simulations (MD) are the models that were used to refine the selection. Based on the structural features of the resorcinol-isoxazole amine NVP-AUY922 (NVP) with significant binding affinity to Hsp90, PBVS enabled the identification of 77 compounds, 10 of which showed favourable binding energy over NVP. Amongst the ten selected compounds, ZINC20411962, ZINC13120102, and ZINC15905860 showed the most favoured interaction with the N-terminus of Hsp90. The root-mean-square deviation (RMSD), root mean square fluctuation (RMSF) and gyration radius (RoG) analyses from the MD simulations confirmed that the three identified compounds are stable at the ATP-binding site of the N-terminus of Hsp90. The MD parameters studied also showed that ZINC20411962 formed the most stable complex with the protein, which was confirmed by the ONIOM calculation with the most negative entropy value of –28 kcal/mol and a binding free energy value of –63 kcal/mol. The compounds interacted with the catalytic residues Thr184, Phe138, Met98 Gly97, and Asn106, which are crucial for the inhibition of Hsp90. The compound ZINC20411962 also has appreciable physicochemical, medicinal, pharmacokinetics, and drug-like properties that could uniquely position it as a potential lead for Hsp90 inhibition. The applied methodology herein represents a promising approach that could pave way for the successful identification of compounds inhibiting crucial targets in diseases, including terminal ones, like cancer.
