(Current Challenges and Updates in Pharmacy Education and Research)

in Silco Virtual Screening, docking and ADMET Prediction of Potential HDAC8 inhibitors

Not scheduled

20m

كلية الصيدلة

Recorded poster Conference Track Three

Speaker

Mr ali mohammed abdulameer

Description

Histone acetylation is a highly interesting epigenetic target for drug therapy. Histone deacetylase enzymes (HDACs) are overexpressed in several diseases including, cancers. Most of the clinically used HDAC inhibitors involve the hydroxamate group as a zinc-binding group (ZBG). Hydroxamates have a poor pharmacokinetic and toxicity profile. Therefore, developing non-hydroximate HDAC inhibitors is a promising strategy for potency and selectivity enhancement.
In this work, we implicated the in silico approaches to design HDAC inhibitors containing new ZBG moiety. We utilized Glide software (Schrodinger Inc.) to perform a high-throughput virtual screening (HTVS) of a Binding Data Bank (BDB) library that contains 22731 scaffolds of possible ZBGs into HDAC8 isoform. The best scoring 290 scaffolds containing heterocyclic or aliphatic ZBGs of a calculated binding affinity of (< -5 kcal/mole) were connected to the linker and cap groups. A standard precision (SP) docking experiment on HDAC8 enzyme was carried out, and the 30 molecules with the highest docking scores of (< 8.5 kcal/mole) were further studied using an extra precision (XP) mode on HDAC1, 2, 4, 6, and 8 to predict the selectivity profile through inspection the binding, fitness, and other parameters from the docking datasheet. For the 7 top molecules, ADMET property prediction was performed using QIKPROP to estimate the toxicity, absorption, distribution, blood-brain barrier penetration, polar surface area, and other pharmacokinetic properties. Compounds with excellent docking profiles and accepted ADMET results were selected for future experimental studies.