Structural exploration of tetrahydroisoquinoline derivatives as HDAC8 inhibitors through multi-QSAR modeling study

Abstract

Abstract Histone deacetylase 8 (HDAC8) is one of the crucial HDACs responsible for influencing the epigenetic functions of the body. Overexpression of HDAC8 is found to be involved in numerous disease conditions such as tumorigenesis, cell proliferation, cancer, viral infections, neuronal disorders and other epigenetic diseases. Therefore, inhibition of HDAC8 is a primary method to combat these diseases. In this article, a multi-QSAR modeling study on tetrahydroisoquinoline derivatives was conducted to identify important contributions of the structural features of these compounds toward HDAC8 inhibition. All these QSAR modeling techniques were individually validated and justified the observations of each other. The results implied that the tetrahydroisoquinoline moiety may be effective as a cap group than as a linker moiety for HDAC8 inhibition. Different substitutions at the tetrahydroisoquinoline scaffold were also found to be crucial in modulating HDAC8 inhibition. Communicated by Ramaswamy H. Sarma