Molecular docking and molecular dynamics of new thioguanine derivatives as histone deacetylase inhibitors

Abstract

Histone deacetylase inhibitors (HDAC-I) comprise structurally diverse molecules that are a group of targeted anticancer agents. Thioguanine is a purine derivative used for the treatment of acute myeloid leukemia. Five new proposed analogs of thioguanine were investigated through molecular docking simulation to assess their binding affinity and therapeutic activity. Molecular dynamics (MD) modeling was conducted for 100 nanoseconds (ns) to investigate the molecular stability of the proposed compounds with the best docking results with histone deacetylase-2 (HDAC-2) and histone deacetylase-8 (HDAC-8) binding pockets. Root mean square deviations (RMSDs) for the ligands and complexes’ initial locations inside the active site have been reported and examined. Lastly, a thorough analysis and evaluation of the interactions between proposed analogs was also performed. The core tetrahedral carbon atom of an amino acid alpha carbon in the protein was used to track the conformational stability of the protein structures to their starting positions. 2-(4-(((6-thioxo-6,7-dihydro-3H-purin-2-yl)imino)methyl)benzoyl)hydrazine-1-carboxamide Compound 2/HDAC-8 complex showed some major fluctuations during simulation time at 17-19 ns; the ligand simulation fluctuated by 4.5 angstroms (Å), and the protein skeleton fluctuated within 2 Å. 2-(4-(((6-thioxo-6,7-dihydro-3H-purin-2-methyl)benzoyl)hydrazine-1-carboxamide Compound 2/HDAC-2 The complex’s RMSD value was within 1.80 Å, indicating good stability inside the target pocket.