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Molecules 2018, 23(12), 3054; https://doi.org/10.3390/molecules23123054

Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches

Division of Life Science, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 21 August 2018 / Revised: 12 November 2018 / Accepted: 14 November 2018 / Published: 22 November 2018
(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)
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Abstract

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease. View Full-Text
Keywords: Chagas disease; Trypanosome cruzi; cruzipian; cysteine protease; molecular docking simulations; molecular dynamics simulations Chagas disease; Trypanosome cruzi; cruzipian; cysteine protease; molecular docking simulations; molecular dynamics simulations
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Rampogu, S.; Lee, G.; Baek, A.; Son, M.; Park, C.; Zeb, A.; Yoon, S.H.; Park, S.; Lee, K.W. Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches. Molecules 2018, 23, 3054.

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