title

طراحی هدفمند محاسباتی ترکیبات ضد سرطان ریه سلول غیر کوچک

محمدنژادی, الهه ، رزاقی اصل, نیما (1401) طراحی هدفمند محاسباتی ترکیبات ضد سرطان ریه سلول غیر کوچک. Journal of Biomolecular Structure and Dynamics ــ 41 (20). ص.ص.10725-10736. شاپا 0739-1102

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عنوان انگليسی

In silico target specific design of potential quinazoline-based anti-NSCLC agents

خلاصه انگلیسی

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. In spite of great advances, treatment of the disease is a medical challenge. Epidermal-growth factor receptor (EGFR) has been taken as a promising cell surface target to develop anti-NSCLC therapies. The main bottleneck to attain clinical efficacy with current EGFR tyrosine kinase inhibitors (EGFR-TKIs) is the rapid spread of oncogenic mutations. Numerous efforts have been made for the synthesis of diverse EGFR-TKIs against resistance-conferring mutations. One of the best strategies to design potent agents would be to explore existing anti-NSCLC drugs at the nonclinical development stage and prioritize privileged structural patterns. Within current study, conformational stability of clinically frequent EGFR mutants (G719S, T790M, L858R and a double mutant form L858R/T790M) were validated via DynaMut and missense3D computational servers. Subsequently, structure activity relationship (SAR) and scaffold similarity inquiry were used to rationally propose a few erlotinib analogues. Intended molecules were subjected to molecular docking and top-scored binders were further analyzed through 50-ns all atom molecular dynamics (MD) simulations to infer the dynamic behavior. The aim was to offer potential binders to overwhelm clinically frequent EGFR-TK mutants. The linear interaction energy (LIE) method was applied to compute the binding free energies between EGFR and intended ligands. For this purpose, MD-based conformational sampling of ligand-enzyme complexes and ligand-water associations were used to acquire thermodynamic energy averages. Though mechanistic details are to be explored, results of the current study identify synthetically accessible quinazoline small molecules with potential affinity toward frequent EGFR-TK mutants.Communicated by Ramaswamy H. Sarma

نوع سند :مقاله
زبان سند : انگلیسی
نویسنده اول :الهه محمدنژادی
نویسنده مسئول :نیما رزاقی اصل
ضریب تاثیر و نمایه مجلات:IF: 4.4 Indexed in: ISI, PubMed/Medline, Scopus, Embase
کلیدواژه ها (انگلیسی):NSCLC - Erlotinib - SAR - Binding - Molecular dynamics
موضوعات :QV فارماکولوژی > QV 744 شیمی دارویی
بخش های دانشگاهی :دانشکده داروسازی > بخش شیمی دارویی
کد شناسایی :16880
ارائه شده توسط : دکتر نیما رزاقی اصل
ارائه شده در تاریخ :06 فروردین 1402 10:44
آخرین تغییر :12 اسفند 1402 10:57

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