Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis

Abstract

Onchocerciasis is the leading cause of blindness and severe skin lesions which remain a major public health problem, especially in tropical areas. The widespread use of antibiotics and the long duration required for effective treatment continues to add to the increasing global menace of multi-resistant pathogens. Onchocerca volvulus harbors the endosymbiont bacteria Wolbachia, essential for the normal development of embryos, larvae and long-term survival of the adult worm, O. volvulus. We report here results of using structure-based drug design (SBDD) approach aimed at identifying potential novel Wolbachia inhibitors from natural products against the Wolbachia surface protein (WSP). The protein sequence of the WSP with UniProtKB identifier Q0RAI4 was used to model the three-dimensional (3D) structure via homology modelling techniques using three different structure-building algorithms implemented in Modeller, I-TASSER and Robetta. Out of the 15 generated models of WSP, one was selected as the most reasonable quality model which had 82, 15.5, 1.9 and 0.5% of the amino acid residues in the most favored regions, additionally allowed regions, generously allowed regions and disallowed regions, respectively, based on the Ramachandran plot. High throughput virtual screening was performed via Autodock Vina with a library comprising 42,883 natural products from African and Chinese databases, including 23 identified anti-Onchocerca inhibitors. The top six compounds comprising ZINC000095913861, ZINC000095486235, ZINC000035941652, NANPDB4566, acetylaleuritolic acid and rhemannic acid had binding energies of −12.7, −11.1, −11.0, −11, −10.3 and −9.5 kcal/mol, respectively. Molecular dynamics simulations including molecular mechanics Poisson-Boltzmann (MMPBSA) calculations reinforced the stability of the ligand-WSP complexes and plausible binding mechanisms. The residues Arg45, Tyr135, Tyr148 and Phe195 were predicted as potential novel critical residues required for ligand binding in pocket 1. Acetylaleuritolic acid and rhemannic acid (lantedene A) have previously been shown to possess anti-onchocercal activity. This warrants the need to evaluate the anti-WSP activity of the identified molecules. The study suggests the exploitation of compounds which target both pockets 1 and 2, by investigating their potential for effective depletion of Wolbachia. These compounds were predicted to possess reasonably good pharmacological profiles with insignificant toxicity and as drug-like. The compounds were computed to possess biological activity including antibacterial, antiparasitic, anthelmintic and anti-rickettsials. The six natural products are potential novel antiwolbachial agents with insignificant toxicities which can be explored further as filaricides for onchocerciasis.

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

“…Also, the coverage of the template sequence to the query is another important factor. Herein, the E -value, sequence identity, query coverage, and the resolution of the 3D structures were used to select the most suitable templates as previously done ( Meier and Söding, 2015 ; Haddad et al., 2020 ; Kwofie et al., 2021 ).…”

“…CASTp predicted 65 potential binding sites of the Ld SMT protein. Ligand binding sites tend to involve the largest pockets or cavities on the protein ( Laskowski et al., 1996 ; Liang et al., 1998 ); thus, pockets with relatively low areas and volumes, such that no ligand could fit, were not considered ( Broni et al., 2021 ; Kwofie et al., 2021 ). A total of seven binding sites were shortlisted ( Supplementary Table 4 ), which were visualized using PyMOL (PyMOL Molecular Graphics System, Version 1.5.0.4, Schrödinger, LLC) ( Lighthall et al., 2010 ) and Chimera 1.16 ( Pettersen et al., 2004 ).…”

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

“…A total of 35,161 natural products from the Traditional Chinese Medicine (TCM) database were obtained from TCM@Taiwan, the world’s largest non-commercial TCM database, which is a catalog of ZINC15 database [ 163 , 241 ]. The compounds were pre-filtered based on molecular weight as previously conducted [ 242 ]. Compounds with molecular weights below 150 g/mol and above 600 g/mol were eliminated.…”

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

“…The drug-likeness of the nine selected compounds was evaluated using Lipinski’s rule of five (Ro5) [ 78 , 79 ]. According to the Ro5, a compound is classified as drug-like and orally active if it conforms to the following criteria: a molecular weight ≤500 Da, an octanol–water partition coefficient log p ≤ 5, HBD ≤ 5, and HBA ≤ 10 [ 79 ].…”