Identification of novel 3-dehydroquinate dehydratase (DHQD) inhibitors for anti-tuberculosis activity: insights from virtual screening, molecular docking, and dynamics simulations.

Abstract

Tuberculosis (TB) remains a pressing global health concern, causing substantial mortality and morbidity despite existing drugs and vaccines. The escalating challenge of drug-resistant TB underscores the critical need for novel medications. This study focuses on the enzyme 3-hydroquinate dehydratase (DHQD) in the shikimate pathway of Mycobacterium tuberculosis (Mtb), essential for Mtb growth. Using an in silico approach, the crystal structure of DHQD complexed with 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) was obtained from the Protein Data Bank. After meticulous preparation, a diverse library of 9699 compounds from Zinc and PubChem databases was subjected to virtual screening, complying with Lipinski's rule of five and compounds capable of binding to DHQD with less binding energy. Molecular docking analysis identified eight compounds with highly favorable binding energies, ranging from -8.99 to -8.39 kcal/mol, surpassing CA's -4.93 kcal/mol. To assess their potential as inhibitors, these eight compounds were subjected to scrutiny for pharmacokinetic properties, encompassing Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) demonstrated desirable pharmacokinetic attributes and were selected for further investigation. Subsequent molecular dynamics (MD) simulations and molecular generalized born surface area (MM-GBSA) analyses were conducted. Molecular dynamics (MD) simulations showed that these five compounds formed stable complexes with DHQD over 50 ns, with root mean square deviation (RMSD) values ranging from 1.57 Å to 2.34 Å, indicating high structural stability. In addition, the MM-GBSA binding energy calculations showed that these compounds had favourable binding affinities, with ZINC14981770 exhibiting the lowest free binding energy of -32.70 kcal/mol, followed by ZINC14741224 at -29.67 kcal/mol and ZINC14743698 at -28.79 kcal/mol. These binding energies significantly outperformed the reference compound CA, which had a binding energy of -10.62 kcal/mol. Based on these findings; these five compounds hold promise as potent inhibitors of Mtb DHQD, pending validation through in vitro and in vivo experiments.