Design (Docking and QSAR Studies) and synthesis of histone deacetylase 2 (HDAC2) inhibitors series

Abstract

In recent years, it has been shown that histone deacetylase 2 (HDAC2) inhibitors increase histone acetylation and enhance memory processes, probably due to an increase in the gene transcription rate that emerges during memory formation. Histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. However, until today there is no specific drug that can target the HDAC2 active site. In this work we applied the method of rational drug design, through enzyme-structural-chemical properties to generate new molecules as HDAC inhibitors. By the application of Quantitative Structure-Activity Relationship (QSAR) and molecular modeling methodologies our aim is to predict more potent HDAC inhibitors. 76 small molecules with potential activity were analyzed using QSAR methodology. The best model was constructed by merging the properties of electronegativity, atomic mass, polarizability, van der Waals forces and some conformational aspects, with the following statistical parameters: r 2 = 0.8935, q 2 LOO-CV = 0.8498, and q 2 LGO-CV = 0.7598. The molecular docking of the ligands on the template was performed by blind docking. The results showed intermolecular interactions between small molecules and some amino acids, such as His145, His146, Asp179, Asp186, and internal-H2O and Zn2+ of which IN01, IN04, and IN14 showed theoretically better biological activity compared with that of TSA and SAHA. Mainly, the IN14 synthesized molecule is a theoretical inhibitor of HDAC class I.