Journal article
Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors
Journal of computer-aided molecular design, v 20(12), pp 789-802
Dec 2006
PMID: 17054015
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
G-protein coupled receptors (GPCRs) comprise a large superfamily of proteins that are targets for nearly 50% of drugs in clinical use today. In the past, the use of structure-based drug design strategies to develop better drug candidates has been severely hampered due to the absence of the receptor’s three-dimensional structure. However, with recent advances in molecular modeling techniques and better computing power, atomic level details of these receptors can be derived from computationally derived molecular models. Using information from these models coupled with experimental evidence, it has become feasible to build receptor pharmacophores. In this study, we demonstrate the use of the Hybrid Structure Based (HSB) method that can be used effectively to screen and identify prospective ligands that bind to GPCRs. Essentially; this multi-step method combines ligand-based methods for building enriched libraries of small molecules and structure-based methods for screening molecules against the GPCR target. The HSB method was validated to identify retinal and its analogues from a random dataset of ∼300,000 molecules. The results from this study showed that the 9 top-ranking molecules are indeed analogues of retinal. The method was also tested to identify analogues of dopamine binding to the dopamine D2 receptor. Six of the ten top-ranking molecules are known analogues of dopamine including a prodrug, while the other thirty-four molecules are currently being tested for their activity against all dopamine receptors. The results from both these test cases have proved that the HSB method provides a realistic solution to bridge the gap between the ever-increasing demand for new drugs to treat psychiatric disorders and the lack of efficient screening methods for GPCRs.
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Details
- Title
- Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors
- Creators
- Sandhya Kortagere - Department of Pharmacology UMDNJ-Robert Wood Johnson Medical School & UMDNJ Informatics Institute 675 Hoes Lane Piscataway NJ 08854 USAWilliam Welsh - Department of Pharmacology UMDNJ-Robert Wood Johnson Medical School & UMDNJ Informatics Institute 675 Hoes Lane Piscataway NJ 08854 USA
- Publication Details
- Journal of computer-aided molecular design, v 20(12), pp 789-802
- Publisher
- Kluwer Academic Publishers; Dordrecht
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000244093900007
- Scopus ID
- 2-s2.0-33947581421
- Other Identifier
- 991014877789304721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics
- Computer Science, Interdisciplinary Applications