کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443441 692722 2013 20 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads
چکیده انگلیسی

Catechol-O-methyltransferase (COMT) catalyzes the methylation of catecholamines, including neurotransmitters like dopamine, epinephrine and norepinephrine, leading to their degradation. COMT has been a subject of study for its implications in numerous neurological disorders like Parkinson's disease (PD), schizophrenia, and depression. The COMT gene is associated with many allelic variants, the Val108Met polymorphism being the most clinically significant.Availability of crystal structure of both 108V and 108M forms of human soluble-COMT (S-COMT) facilitated us to use structure-based virtual screening approach to obtain new hits by screening a library of CNS permeable compounds from ZINC database. In this study, E-pharmacophore was also used to generate pharmacophore models based on a series of known COMT inhibitors. A five-point pharmacophore model consisting of one hydrogen-bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R) was generated for both the polymorphic forms of COMT. These models were then used for filtering ZINC-CNS permeable library to obtain new hits. Physicochemical properties were also calculated for all the hits obtained from both the approaches for favorable ADME properties. These identified hits maybe of interest for further structural optimization and biological evaluation assays.

Figure optionsDownload high-quality image (177 K)Download as PowerPoint slideHighlights
► Structures of both the polymorphic forms (108V and 108M) of S-COMT taken for study.
► Database screening by structure based docking done.
► Pharmacophore generation using known COMT inhibitors and screening.
► The hits obtained from both the approaches were reported for further lead optimization.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 39, February 2013, Pages 145–164
نویسندگان
, , ,