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Identification of Hot Spots within Druggable Binding Regions by Computational Solvent Mapping of Proteins
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Section:Abstract
Here we apply the computational solvent mapping (CS-Map) algorithm toward the in silico identification of hot spots, that is, regions of protein binding sites that are major contributors to the binding energy and, hence, are prime targets in drug design. The CS-Map algorithm, developed for binding site characterization, moves small organic functional groups around the protein surface and determines their most energetically favorable binding positions. The utility of CS-Map algorithm toward the prediction of hot spot regions in druggable binding pockets is illustrated by three test systems: (1) renin aspartic protease, (2) a set of previously characterized druggable proteins, and (3) E. coli ketopantoate reductase. In each of the three studies, existing literature was used to verify our results. Based on our analyses, we conclude that the information provided by CS-Map can contribute substantially to the identification of hot spots, a necessary predecessor of fragment-based drug discovery efforts.
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This article has been cited by 11 ACS Journal articles (5 most recent appear below).
Hot Spot Analysis for Driving the Development of Hits into Leads in Fragment-Based Drug Discovery
David R. Hall, Chi Ho Ngan, Brandon S. Zerbe, Dima Kozakov, and Sandor VajdaJournal of Chemical Information and Modeling2012 52 (1), 199-209Hot Spot Analysis for Driving the Development of Hits into Leads in Fragment-Based Drug Discovery
David R. Hall, Chi Ho Ngan, Brandon S. Zerbe, Dima Kozakov, and Sandor VajdaJournal of Chemical Information and Modeling2012 52 (1), 199-209Fragment-based drug design (FBDD) starts with finding fragment-sized compounds that are highly ligand efficient and can serve as a core moiety for developing high-affinity leads. Although the core-bound structure of a protein facilitates the construction ...
Robust Identification of Binding Hot Spots Using Continuum Electrostatics: Application to Hen Egg-White Lysozyme
David H. Hall, Laurie E. Grove, Christine Yueh, Chi Ho Ngan, Dima Kozakov, and Sandor VajdaJournal of the American Chemical Society2011 133 (51), 20668-20671Robust Identification of Binding Hot Spots Using Continuum Electrostatics: Application to Hen Egg-White Lysozyme
David H. Hall, Laurie E. Grove, Christine Yueh, Chi Ho Ngan, Dima Kozakov, and Sandor VajdaJournal of the American Chemical Society2011 133 (51), 20668-20671Binding hot spots, protein regions with high binding affinity, can be identified by using X-ray crystallography or NMR spectroscopy to screen libraries of small organic molecules that tend to cluster at such hot spots. FTMap, a direct computational ...
AADS - An Automated Active Site Identification, Docking, and Scoring Protocol for Protein Targets Based on Physicochemical Descriptors
Tanya Singh, D. Biswas, and B. JayaramJournal of Chemical Information and Modeling2011 51 (10), 2515-2527AADS - An Automated Active Site Identification, Docking, and Scoring Protocol for Protein Targets Based on Physicochemical Descriptors
Tanya Singh, D. Biswas, and B. JayaramJournal of Chemical Information and Modeling2011 51 (10), 2515-2527We report here a robust automated active site detection, docking, and scoring (AADS) protocol for proteins with known structures. The active site finder identifies all cavities in a protein and scores them based on the physicochemical properties of ...
Reproducing Crystal Binding Modes of Ligand Functional Groups Using Site-Identification by Ligand Competitive Saturation (SILCS) Simulations
E. Prabhu Raman, Wenbo Yu, Olgun Guvench, and Alexander D. MacKerell, Jr.Journal of Chemical Information and Modeling2011 51 (4), 877-896Reproducing Crystal Binding Modes of Ligand Functional Groups Using Site-Identification by Ligand Competitive Saturation (SILCS) Simulations
E. Prabhu Raman, Wenbo Yu, Olgun Guvench, and Alexander D. MacKerell, Jr.Journal of Chemical Information and Modeling2011 51 (4), 877-896The applicability of a computational method, Site Identification by Ligand Competitive Saturation (SILCS), to identify regions on a protein surface with which different types of functional groups on low-molecular weight inhibitors interact is ...
Drug-like Density: A Method of Quantifying the “Bindability” of a Protein Target Based on a Very Large Set of Pockets and Drug-like Ligands from the Protein Data Bank
Robert P. Sheridan, Vladimir N. Maiorov, M. Katharine Holloway, Wendy D. Cornell, and Ying-Duo GaoJournal of Chemical Information and Modeling2010 50 (11), 2029-2040Drug-like Density: A Method of Quantifying the “Bindability” of a Protein Target Based on a Very Large Set of Pockets and Drug-like Ligands from the Protein Data Bank
Robert P. Sheridan, Vladimir N. Maiorov, M. Katharine Holloway, Wendy D. Cornell, and Ying-Duo GaoJournal of Chemical Information and Modeling2010 50 (11), 2029-2040One approach to estimating the “chemical tractability” of a candidate protein target where we know the atomic resolution structure is to examine the physical properties of potential binding sites. A number of other workers have addressed this issue. We ...
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Accession Codes
- PDB: 1RNE
- PDB: 1BIL
- PDB: 1BIM
- PDB: 1HRN
- PDB: 2REN
- PDB: 1E31
- PDB: 1H10
- PDB: 1IU0
- PDB: 1I8H
- PDB: 1FKJ
- PDB: 1FKT
- PDB: 1FV9
- PDB: 1G4K
- PDB: 3USN
- PDB: 1QAM
- PDB: 1RD4
- PDB: 1DGQ
- PDB: 1UAE
- PDB: 1YCR
- PDB: 1PTY
- PDB: 1PH0
- PDB: 1FKD
- PDB: 1QPF
- PDB: 1QPL
- PDB: 1KS9
- PDB: 1YJQ
- PDB: 1YON
History
- Published In Issue March 22, 2007
- Received September 28, 2006
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