The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the
third step of the shikimate pathway in <i>Mycobacterium
tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate.
In this study, the novel inhibitors of DHQase from MTB was identified using in
silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic
acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure
prepared through energy minimization and structure optimization. A total of
9699 compounds obtained from Zinc and PubChem databases capable of binding to
DHQase and subjected to virtual screening through Lipinski’s rule of five and
molecular docking analysis. Eight (8) compounds with good binding energies,
ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding
energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic
properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or
ADMET). Five compounds (ZINC14981770, ZINC14741224,
ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic
properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA)
analyses. The results of the analyses showed that all the compounds
formed stable and rigid complexes after the 50ns MD simulation and also had a
lower binding as compared to CA. Therefore, these compounds considered as good
inhibitors of MTB after in vitro and in vivo validation.”
Combining species specific in vitro & in silico models to predict in vivo food effect in a preclinical stage – case study of Venetoclax
