Implication of Ab Initio, QM/MM, and molecular dynamics calculations on the prediction of the therapeutic potential of some selected HDAC inhibitors

Abstract

ABSTRACT Epigenetics regulates gene expression through post-translational modification of protein complexes accompanying DNA. The most significant modification in histone protein is deacetylation, regulated by HDAC enzyme. This study focuses on the HDAC inhibitors' effect on the HDLP enzyme's stability. Ab initio quantum mechanics (QM), Quantum mechanics/molecular mechanics (QM/MM), and Molecular dynamics (MD) analyses were executed to investigate the changes that occur in the HDLP enzyme due to inhibitor binding. LBH589, PCI24781, PXD101, LAQ824, SB939, and RAS2410 were selected as inhibitors, and SAHA was used as a reference inhibitor. The crystal structure of the HDLP enzyme was obtained from the Protein Data Bank, and the inhibitor structures were optimized using G09W. AutoDock-Vina was used to perform docking, and the resultant complex was used to perform MD simulation. The QM/MM two-layer binding energy studies revealed that the stabilities of HDLP-LBH589 and HDLP-PCI24781 are higher than the other studied complexes. Also, it was found that the pKa values of the inhibitors are correlated with their binding energy. Further, the trajectory analysis results showed that the complexes of HDLP with LBH589, PCI24781, and SAHA are comparatively more stable. Therefore, it is concluded that LBH589 and PCI24781 are excellent candidates to be studied as HDLP inhibitors.