مدل سازی جزئی مولکولی-اتمی یک مهار کننده قوی p38 آلفا نوع2

احمد, عبادی and رزاقی اصل, نیما and مهدی, خوشنویس زاده and رامین, میری (1394) مدل سازی جزئی مولکولی-اتمی یک مهار کننده قوی p38 آلفا نوع2. Structural Chemistry ــ 26 (4). pp. 1125-1137. شاپا 0400-1040

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Official URL: http://link.springer.com/article/10.1007%2Fs11224-...


Detailed atomistic molecular modeling of a potent type ΙΙ p38α inhibitor

English Abstract

The active site conservation among protein kinases makes it a real challenge to design selective inhibitors. In this regard, detailed understanding of structural features responsible for functional behavior of different protein kinases is an important challenge in structure-based drug design. Amino acid decomposition analysis (ADA) is a powerful method to recognize and evaluate possible binding loci (hot spots) in ligand–receptor interaction. These hot spots could be used as a tool to differentiate selectivity profiles among similar protein kinases. p38a is a prominent target in the development of new anti-inflammatory agents. Type II p38a inhibitors bind to DFG-out conformation of p38a in its inactive form. We performed a computational approach including MD simulations and ab initio method to evaluate a type II p38a inhibitor. MD simulation was used to evaluate the binding pattern between ligand and p38a active site residues. Penetration of ligand thorough lipid bilayer was assessed by MD simulation using DPPC as a lipid bilayer model. Further conformational analysis was applied to determine induced ligand conformational instability due to binding to the receptor. ADA provided interesting results for pharmacophore discrimination. According to obtained results, residues Asp168, Leu167, Met109 and Glu71 had most contribution in binding to ligand. Conformational analysis showed that diffusion of ligand through lipid bilayer is done almost in nearly optimum structure. The obtained results could reveal some information on molecular basis of p38a inhibition, while being in good agreement with proposed pharmacophore in the literature.

Item Type:Article
زبان سند : انگلیسی
نویسنده اول :عبادی احمد
نویسنده :نیما رزاقی اصل
نویسنده :خوشنویس زاده مهدی
نویسنده :میری رامین
Additional Information:Impact Factor(2015):1.854 Indexed in: ISI, Scopus, Chemical Abstracts Service (CAS),Google Scholar, Academic OneFile, Chimica, CNKI, Current Abstracts, Current Contents/Physical, Chemical and Earth Sciences, EBSCO Academic Search, EBSCO Engineering Source
کلیدواژه ها (انگلیسی):p38α MAPK, Molecular dynamics, Ab initio, Conformational analysis
Subjects:QV pharmacology > QV 744 Medicinal Chemistry
Divisions:School of Pharmacy > Department of Medicinal Chemistry
ID Code:5373
Deposited By: Dr Nima Razzaghi-Asl
Deposited On:10 May 1394 06:44
Last Modified:12 Dec 1396 08:42

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