title

شاخص های نظری باندینگ لیگاند-رسپتور در طراحی مولکول های زیست فعال

رزاقی اصل, نیما and میری, رامین and عبادی, احمد and ادراکی, نجمه and شهابی پور, سارا (1391) شاخص های نظری باندینگ لیگاند-رسپتور در طراحی مولکول های زیست فعال. Research in Pharmaceutical Sciences ــ 7 (supll5). S614-S614. شاپا 1735-9414

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Title

Theoretical binding efficiencies in bioactive molecular design: a case study on BACE-1 inhibitors

English Abstract

Background and Aims: Beta site amyloid precursor protein cleaving enzyme-1 (BACE-1) is an important membrane associated protein responsible for formation of amyloid plaques causing alzheimer. Peptidic/nonpeptidic inhibitors of this key protease have been developed up to now. Small molecule BACE-1 inhibitors have been considered due to the pharmacokinetic problems of peptidic inhibitors. In this study, small molecule BACE-1 inhibitors were subjected to dissection analysis and constitutional fragments considering atom type, hybridization, and bond order were generated. These simplified structures were assessed in terms of binding to the BACE-1 active site through a validated docking procedure. Methods: Autodock4.2 program was applied to conduct a docking simulation method. All the preprocessing steps for ligands and receptor were performed by AutoDock Tools and What IF server. Results: Isophthalamide scaffold was found to be an appropriate scaffold for further bioactive molecular modifications. Other following efficient scaffolds contained arylpiperazine, imidazolidinone, pyrimidinone and benzoimidazole. The ways these findings might be beneficial to guide rational bioactive molecular development strategies were suggested. Conclusions: Shape-based dissection analysis was applied to dissect BACE-1 inhibiting structures. The classification route was followed by a fragment-based docking strategy to rank the structural features of BACE- 1 inhibitors. Our case study confirmed that evaluation of the ligand-receptor interactions on the basis of ligand binding efficiency indices rather than the mere free energy of binding could be a helpful strategy in recognizing potential candidates for further bioactive molecular design. Moreover; various efficiency parameters of simplified BACE-1 inhibiting structures obtained on the basis of docking calculation were in good agreement with each other. Our case study re-consolidated that designing larger structures may require special attention toward efficiency indices incorporating MW rather than number of heavy atoms. This technique leads to more realistic view at the individual atom participations in binding to the receptor.

Item Type:Article
زبان سند : انگلیسی
نویسنده مسئول :نیما رزاقی اصل
نویسنده :رامین میری
نویسنده :احمد عبادی
نویسنده :نجمه ادراکی
نویسنده :سارا شهابی پور
Additional Information:Journal Indexing : Research in Pharmaceutical Sciences (RPS) is visible in Thomson Reuters ISI Web of Knowledge and is indexed by PubMed and PubMed central and abstracted in the Elsevier Bibliographic Databases. Databases include Scopus, EMBASE, EMCare, EMBiology and Elsevier BIOBASE. It is also indexed in several specialized databases including Scientific Information Database (SID), Google Scholar, Iran Medex, Magiran, Index Copernicus (IC) and Islamic World Science Citation Center (ISC)
کلیدواژه ها (انگلیسی):Alzheimer; Dissection analysis; Docking; Binding efficiency
Subjects:QV pharmacology > QV 744 Medicinal Chemistry
Divisions:School of Pharmacy > Department of Medicinal Chemistry
ID Code:5387
Deposited By: Dr Nima Razzaghi-Asl
Deposited On:10 Sep 1393 07:20
Last Modified:10 Sep 1393 07:20

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