Structural insights of WBmDapE and deciphering of potent anti-filarial inhibitors: a state-of-art computational approach.

Lymphatic filariasis (LF) stands as a debilitating tropical ailment, impacting a considerable global populace. Existing drug therapies for LF exhibit limited effectiveness across all parasite stages, thereby accentuating the imperative for novel anti-filarial medications characterized by enhanced prognostic attributes and minimized adverse reactions. A promising avenue involves targeting the microbial enzyme WBmDapE, pivotal in worm survival and intricately linked to the lysine biosynthetic pathway and peptidoglycan cell wall construction. This investigation employs in silico methodologies encompassing molecular docking, Molecular Dynamics Simulation (MDS), conformational analysis, Shape-Based Virtual Screening (SBVS), ADMETox, MMGBSA, and Density Functional Theory (DFT) calculations to discern potential inhibitors of WBmDapE. Through discerning the conformational shifts of the WBmDapE-bound substrate and product, key amino acids implicated in substrate binding (Arg182 and Asp248) are unveiled. While the apo and substrate-bound structures exhibit an open conformation, the product-bound structure displays marked conformational alterations, including shifts within the catalytic domain and the cofactor in the dimerization domain, suggestive of an active and closed conformation. From the prism of shape-based virtual screening, two preeminent compounds (ZINC42784280 and ZINC84308049) have surfaced as potential hits. These compounds evince heightened binding affinity, optimal binding free energy, pivotal hydrogen bond interactions, and akin attributes to the product-bound complex. Subsequently, these compounds emerge as prospective candidates for filariasis treatment. In summation, our study furnishes invaluable insights into the fabrication of innovative WBmDapE inhibitors, potentially serving as anti-filarial agents. Rigorous experimental substantiation and fine-tuning of these compounds are requisite for prospective therapeutic interventions against LF.