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

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-resist...

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Autores principales:	Samuel K. Kwofie, Emmanuel Broni, Faruk U. Yunus, John Nsoh, Dela Adoboe, Whelton A. Miller, Michael D. Wilson
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	onchocerciasis <i>Onchocerca volvulus</i> <i>Wolbachia</i> surface protein structure-based drug design natural product Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/94152e704d4e499d93a0a74fe509321d
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spelling	oai:doaj.org-article:94152e704d4e499d93a0a74fe509321d2021-11-25T16:50:46ZMolecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis10.3390/biomedicines91116822227-9059https://doaj.org/article/94152e704d4e499d93a0a74fe509321d2021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1682https://doaj.org/toc/2227-9059Onchocerciasis 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. <i>Onchocerca volvulus</i> harbors the endosymbiont bacteria <i>Wolbachia</i>, essential for the normal development of embryos, larvae and long-term survival of the adult worm, <i>O. volvulus</i>. We report here results of using structure-based drug design (SBDD) approach aimed at identifying potential novel <i>Wolbachia</i> inhibitors from natural products against the <i>Wolbachia</i> 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-<i>Onchocerca</i> 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 <i>Wolbachia</i>. 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.Samuel K. KwofieEmmanuel BroniFaruk U. YunusJohn NsohDela AdoboeWhelton A. MillerMichael D. WilsonMDPI AGarticleonchocerciasis<i>Onchocerca volvulus</i><i>Wolbachia</i> surface proteinstructure-based drug designnatural productBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1682, p 1682 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	onchocerciasis <i>Onchocerca volvulus</i> <i>Wolbachia</i> surface protein structure-based drug design natural product Biology (General) QH301-705.5
spellingShingle	onchocerciasis <i>Onchocerca volvulus</i> <i>Wolbachia</i> surface protein structure-based drug design natural product Biology (General) QH301-705.5 Samuel K. Kwofie Emmanuel Broni Faruk U. Yunus John Nsoh Dela Adoboe Whelton A. Miller Michael D. Wilson Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
description	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. <i>Onchocerca volvulus</i> harbors the endosymbiont bacteria <i>Wolbachia</i>, essential for the normal development of embryos, larvae and long-term survival of the adult worm, <i>O. volvulus</i>. We report here results of using structure-based drug design (SBDD) approach aimed at identifying potential novel <i>Wolbachia</i> inhibitors from natural products against the <i>Wolbachia</i> 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-<i>Onchocerca</i> 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 <i>Wolbachia</i>. 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.
format	article
author	Samuel K. Kwofie Emmanuel Broni Faruk U. Yunus John Nsoh Dela Adoboe Whelton A. Miller Michael D. Wilson
author_facet	Samuel K. Kwofie Emmanuel Broni Faruk U. Yunus John Nsoh Dela Adoboe Whelton A. Miller Michael D. Wilson
author_sort	Samuel K. Kwofie
title	Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
title_short	Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
title_full	Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
title_fullStr	Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
title_full_unstemmed	Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis
title_sort	molecular docking simulation studies identifies potential natural product derived-antiwolbachial compounds as filaricides against onchocerciasis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/94152e704d4e499d93a0a74fe509321d
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Molecular Docking Simulation Studies Identifies Potential Natural Product Derived-Antiwolbachial Compounds as Filaricides against Onchocerciasis

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