Rational drug design of histone deacetylase 6 inhibitors

Abstract

Activity of the histone deacetylases (HDACs) has an essential influence on histone posttranslational modifications. Therefore, alterations in the structure and expression of HDACs isoforms are strongly related to the pathogenesis of inflammation, cancer, and neurodegeneration. The HDACs became extensively examined targets in novel drug discovery. The HDAC6 isoform is a non-histone cytoplasmic deacetylase, manly involved in deacetylation of α-tubulin, cortactin, and heat shock protein 90 (Hsp90) [1]. Our rational drug design study was focused on identification of selective histone deacetylase 6 (HDAC6) inhibitors by use of combined ligand and structure based methodologies. Based on the 3D-QSAR (Quantitative Structure Activity Relationship) modeling of HDAC6 inhibitors were defined specific molecular determinants for selective HDAC6 inhibition and further applied for fragment based design of selective HDAC6 inhibitors. Recently resolved crystal structure of second human catalytic domain of HDAC-6 enzyme (5EDU) [2] was used in virtual docking study of the examined inhibitors.