Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors |
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Authors: | Sandhya Kortagere William J Welsh |
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Institution: | (1) Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School & UMDNJ Informatics Institute, 675 Hoes Lane, Piscataway, NJ 08854, USA |
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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.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. |
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Keywords: | GPCRs Virtual screening Structure-based methods Shape Signatures Dopamine receptors Scoring functions |
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