Diarylcyclopropane hydroxamic acid inhibitors of histone deacetylase 4 designed by combinatorial approach and QM/MM calculations

Publication date: Available online 16 August 2018Source: Journal of Molecular Graphics and ModellingAuthor(s): Jakub Kollar, Vladimir FrecerAbstractInhibitors of histone deacetylase superfamily (HDAC), which induce cell cycle arrest, trigger cell death and reduce angiogenesis appear as promising anti-cancer drugs targeting the epigenetic regulation of gene expression. Approved HDAC inhibitors were found effective against haematological and solid malignancies, other HDACIs are currently in clinical trials for the treatment of neurological diseases or immune disorders. Among those, diarylcyclopropane hydroxamic acids (DCHA) were found to be potent and selective inhibitors of the class IIa HDACs, specifically HDAC4, a pharmacological target for the treatment of Huntington's disease and muscular atrophy. Crystallographic analysis revealed that one of the aryl groups of the DCHA fills the lower specificity pocket of the HDAC4 catalytic site that is specific for the class IIa HDACs. We have used computer-assisted combinatorial chemistry, hybrid quantum mechanics/molecular mechanics (QM/MM) with implicit solvation and QSAR models to optimize DCHA inhibitors and propose more potent DCHA analogues. The QM/MM approach has been selected since the process of inhibitor binding to the catalytic zinc and polar amino acid residues of the deacetylase active site induces considerable rearrangement of electron density of the inhibitor. Virtual combinatorial library consisting of 12180 DCHA anal...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research