Design of novel small molecules derived from styrylpyridine as potent HDAC1 inhibitors for the treatment of gastric cancer using 3D-QSAR, drug similarity, ADMET prediction, molecular docking, and molecular dynamics studies

Histone deacetylase (HDAC) dysregulation plays an important role in cancer progression and is an important therapeutic target for anticancer drug development. A series of molecules derived from styrylpyridine have HDAC inhibitory activity for the treatment of gastric cancer and could have great potential as drugs against gastric cancer. The objective of this work is to modify the styrylpyridine backbone in order to design new inhibitors with high activity and favorable pharmacokinetic properties for drug discovery. Based on the three-dimensional quantitative structure- activity study, robust and reliable comparative molecular field analysis and comparative molecular similarity index analysis models were developed and validated, then used to design seven new molecules and predict in silico their biological activity. As a result, the seven newly designed molecules have a higher biological activity than the synthesized template molecule N21. The designed molecules are submitted to tests for drug -like properties, pharmacokinetics properties, and molecular docking. These tests enabled us to select the two newly -designed molecules T5 and T6 as the best HDAC1 inhibitors, compared with the model molecule N21. Subsequently, molecular dynamics simulations were carried out to study the stability of styrylpyridine derivatives in the active site of HDAC1. The designed molecules T5 and T6 have the potential to be drugs for treating gastric cancer. The synthesis, in vitro and in vivo evaluation of the biological activity of newly designed molecules T5 and T6 are interesting proposal for the conception of new drugs to treat gastric cancer.