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Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor
Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the develop...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843766/ https://www.ncbi.nlm.nih.gov/pubmed/31581577 http://dx.doi.org/10.3390/biom9100556 |
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author | Veeramachaneni, Ganesh Kumar Thunuguntla, V B S C Bhaswant, Maharshi Mathai, Michael L. Bondili, Jayakumar Singh |
author_facet | Veeramachaneni, Ganesh Kumar Thunuguntla, V B S C Bhaswant, Maharshi Mathai, Michael L. Bondili, Jayakumar Singh |
author_sort | Veeramachaneni, Ganesh Kumar |
collection | PubMed |
description | Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the development of new drugs aiming at satiety and appetite control targets. Among the reported satiety signaling targets, 5HT(2C) receptor plays a crucial role in decreasing appetite and has become a promising target for the development of anti-obesity drugs. Lorcaserin, a 5HT(2C) receptor agonist and the only drug available in the market, was designed based on the receptor mechanism of action. Due to limited drug options available and considering the adverse drug effects of Lorcaserin, the development of new drugs which are highly specific toward the 5HT(2C) target and with lesser side effects is essential. The present study is majorly focused on developing new 5HT(2C) agonists through computational approaches like screening, docking, and simulation using Phase, QikProp, Glide and Desmond applications of the Schrodinger suite. Screening protocols resulted in eight best hit molecules with affinity for the receptor and among them, five hits displayed binding affinity toward the conserved residue Asp 134 of the receptor. The stability of the five molecules in complex with the 5HT(2C) receptor was studied through molecular dynamic simulations. Three molecules, ZINC32123870, ZINC40312983 and ZINC32124535, maintained stable interactions with the Asp 134 residue throughout the 50 ns simulation run time. Further, due to the high sequence similarity seen among the receptors of 5HT2 family, the three potential hits were cross validated against other subtypes 5HT(2A) and 5HT(2B) of the 5HT2 family to determine the specificity of the molecules against the target. Among the three hits, ZINC32124535 was identified as the best potential hit based on the hydrogen bond interaction percentage with Asp residue [5HT(2A) (Asp 155:60%); 5HT(2B) (Asp155: No interaction); 5HT(2C) (Asp 134:86%)]. The ZINC32124535 molecule produced one salt bridge and hydrogen bond interactions with Asp 134, alike the known drug Lorcaserin. Based on the results, ZINC32124535 was identified as the best potential hit against the 5HT(2C) receptor. |
format | Online Article Text |
id | pubmed-6843766 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68437662019-11-25 Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor Veeramachaneni, Ganesh Kumar Thunuguntla, V B S C Bhaswant, Maharshi Mathai, Michael L. Bondili, Jayakumar Singh Biomolecules Article Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the development of new drugs aiming at satiety and appetite control targets. Among the reported satiety signaling targets, 5HT(2C) receptor plays a crucial role in decreasing appetite and has become a promising target for the development of anti-obesity drugs. Lorcaserin, a 5HT(2C) receptor agonist and the only drug available in the market, was designed based on the receptor mechanism of action. Due to limited drug options available and considering the adverse drug effects of Lorcaserin, the development of new drugs which are highly specific toward the 5HT(2C) target and with lesser side effects is essential. The present study is majorly focused on developing new 5HT(2C) agonists through computational approaches like screening, docking, and simulation using Phase, QikProp, Glide and Desmond applications of the Schrodinger suite. Screening protocols resulted in eight best hit molecules with affinity for the receptor and among them, five hits displayed binding affinity toward the conserved residue Asp 134 of the receptor. The stability of the five molecules in complex with the 5HT(2C) receptor was studied through molecular dynamic simulations. Three molecules, ZINC32123870, ZINC40312983 and ZINC32124535, maintained stable interactions with the Asp 134 residue throughout the 50 ns simulation run time. Further, due to the high sequence similarity seen among the receptors of 5HT2 family, the three potential hits were cross validated against other subtypes 5HT(2A) and 5HT(2B) of the 5HT2 family to determine the specificity of the molecules against the target. Among the three hits, ZINC32124535 was identified as the best potential hit based on the hydrogen bond interaction percentage with Asp residue [5HT(2A) (Asp 155:60%); 5HT(2B) (Asp155: No interaction); 5HT(2C) (Asp 134:86%)]. The ZINC32124535 molecule produced one salt bridge and hydrogen bond interactions with Asp 134, alike the known drug Lorcaserin. Based on the results, ZINC32124535 was identified as the best potential hit against the 5HT(2C) receptor. MDPI 2019-10-01 /pmc/articles/PMC6843766/ /pubmed/31581577 http://dx.doi.org/10.3390/biom9100556 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Veeramachaneni, Ganesh Kumar Thunuguntla, V B S C Bhaswant, Maharshi Mathai, Michael L. Bondili, Jayakumar Singh Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title | Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title_full | Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title_fullStr | Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title_full_unstemmed | Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title_short | Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT(2C) Receptor |
title_sort | pharmacophore directed screening of agonistic natural molecules showing affinity to 5ht(2c) receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843766/ https://www.ncbi.nlm.nih.gov/pubmed/31581577 http://dx.doi.org/10.3390/biom9100556 |
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