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

被引：17

作者：

Durdagi, Serdar ^{[1
,11
]}

Aksoydan, Busecan ^{[1
,11
]}

Erol, Ismail ^{[1
,2
]}

Kantarcioglu, Isik ^{[1
,7
]}

Ergun, Yavuz ^{[3
]}

Bulut, Gulay ^{[4
]}

Acar, Melih ^{[5
]}

Avsar, Timucin ^{[5
]}

Liapakis, George ^{[6
]}

Karageorgos, Viasios ^{[6
]}

Salmas, Ramin E. ^{[1
]}

Sergi, Baris ^{[4
]}

Alkhatib, Sara ^{[7
]}

Turan, Gizem ^{[8
]}

Yigit, Berfu Nur ^{[8
]}

Cantasir, Kutay ^{[9
]}

Kurt, Bahar ^{[9
]}

Kilic, Turker ^{[10
]}

机构：

[1] Bahcesehir Univ BAU, Sch Med, Dept Biophys, Computat Biol & Mol Simulat Lab, Istanbul, Turkey

[2] Gebze Tech Univ, Dept Chem, Kocaeli, Turkey

[3] Dokuz Eylul Univ, Dept Chem, Izmir, Turkey

[4] Bahcesehir Univ, Dept Mol Biol & Genet, Istanbul, Turkey

[5] Bahcesehir Univ BAU, Sch Med, Dept Med Biol, Istanbul, Turkey

[6] Univ Crete, Dept Pharmacol, Fac Med, Iraklion, Greece

[7] Bahcesehir Univ, Grad Sch Nat & Appl Sci, Bioengn Program, Istanbul, Turkey

[8] Bahcesehir Univ, Grad Sch Hlth Sci, Neurosci Program, Istanbul, Turkey

[9] Bahcesehir Univ, Sch Med, Istanbul, Turkey

[10] Bahcesehir Univ, Sch Med, Dept Neurosurg, Istanbul, Turkey

[11] Bahcesehir Univ, Grad Sch Hlth Sci, Neurosci Program, Istanbul, Turkey

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 145卷

关键词：

AT1; receptor; Virtual screening; Docking; MD simulations; Synthesis; Wound healing; Cell cycle analysis; Binary QSAR models; II RECEPTOR ANTAGONISTS; PROTEIN-LIGAND COMPLEXES; DRUG-LIKE MOLECULES; 1 AT(1) ANTAGONISTS; BIOLOGICAL EVALUATION; COMPUTATIONAL APPROACH; DYNAMICS SIMULATIONS; NMR-SPECTROSCOPY; ACCURATE DOCKING; AT1; ANTAGONISTS;

D O I：

10.1016/j.ejmech.2017.12.021

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：273 / 290

页数：18

共 67 条

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