The search for potential isoform-selective histone deacetylase inhibitors via structure-based virtual screening
Abdullahi Ibrahim Uba and Kemal Yelekci
Kadir Has University, Turkey
Bayero University, Nigeria
: J Pharm Sci Emerg Drugs
Abstract
Histone deacetylases (HDACs) have gained increased attention as targets for anticancer drug design and development. HDAC inhibitors have proven to be effective for reversing the malignant phenotype in HDACdependent cancer cases. However, lack of selectivity of the many HDAC inhibitors in clinical use and trials is causes adverse effect. It is believed that, the continued identification of isoform-selective inhibitors will eliminate these undesirable adverse effects — a task that remains a major challenge due to high structural similarity around the HDACs active site. The present work attempted to identify isoform-selective inhibitors of individual members of class I HDACs by screening a large compound library containing ~ 200,000 compounds retrieved from Otava database. We identified a total of 40 compounds with high isoform selectivity and these compounds passed drug-likeness and absorption, distribution, metabolism, elimination and toxicity prediction tests. Furthermore, to study the stability of ligand binding modes, 10 ns-molecular dynamics (MD) simulations of the free HDAC isoforms and their complexes with respective best-ranked ligands were performed using nanoscale molecular dynamics (NAMD) software. The inhibitors remained bound to their respective targets over time of the simulation and the overall potential energy, root-mean-square deviation, root-mean-square fluctuation profiles suggested that the predicted inhibitors may be potential isoform-selective inhibitors or serve as promising lead compounds for further optimization.
Biography
E-mail: abdullahi.iu2@gmail.com
