Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation
| Autor: | George Liapakis, Sara Alkhatib, Yavuz Ergun, Berfu Nur Yigit, Gülay Bulut, Melih Acar, Busecan Aksoydan, Ismail Erol, Ramin Ekhteiari Salmas, Bahar Kurt, Vlasios Karageorgos, Turker Kilic, Isik Kantarcioglu, Kutay Cantasir, Serdar Durdagi, Gizem Turan, Timuçin Avşar, Barış Sergi |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Cell cycle checkpoint Antineoplastic Agents Pharmacology 01 natural sciences Mice Structure-Activity Relationship 03 medical and health sciences Drug Discovery Animals Humans Receptor Antihypertensive Agents Cells Cultured Cell Proliferation Virtual screening Angiotensin II receptor type 1 Cell Death Dose-Response Relationship Drug Molecular Structure Chemistry Cell growth Drug discovery Organic Chemistry Imidazoles Oxazolone Cell Cycle Checkpoints General Medicine Angiotensin II Ether-A-Go-Go Potassium Channels 0104 chemical sciences 010404 medicinal & biomolecular chemistry 030104 developmental biology Docking (molecular) NIH 3T3 Cells Drug Screening Assays Antitumor |
| Zdroj: | European Journal of Medicinal Chemistry. 145:273-290 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.12.021 |
| Popis: | AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents - due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor. In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [I-125-Sar(1)-Ile(8)] AngII. Among the compounds tested, 19d and 9j molecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule 19d led to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. (C) 2017 Elsevier Masson SAS. All rights reserved. |
| Databáze: | OpenAIRE |
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