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Dr. PETER KOLB
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Address 1
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Address 2
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Title
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Dr.
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First Name
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PETER
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Last Name
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KOLB
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University/Institution
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Philipps-University Marburg
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Email ID
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pkolb@postdocjournal.com
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City
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Marburg
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Country
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Germany
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State
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Hesse
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Zipcode
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35032
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Department
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Pharmaceutical Chemistry
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Company Name
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Area of Research
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Computer-aided structure based ligand design
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Area of Expertise
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Drugs, Structure-based methods, chemoinformatics
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Brief Description of Research Interest :
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As a graduate student in the lab of Amedeo Caflisch at the University of Zurich, I developed fragment-based docking approaches. My most important contribution was DAIM (Decomposition And Identification of Molecules), a software to decompose large databases of small molecules. DAIM selects fragments as potential anchors to orient a small molecule in a binding site and thus makes high-throughput docking possible. Based on DAIM, I developed ALTA (Anchor-based Library Tailoring), which uses pharmacophoric binding site constraints to effectively generate a target-specific molecular library on the fly, thereby substantially reducing calculation times. Finally, using the LIECE (Linear Interaction Energy with Continuum Electrostatics) method of re-ranking docking results, I showed that it is possible to transfer the scoring function parameters between kinases.
Combining the three above-mentioned methodological advances, I identified eight ligands for the kinase EphB4 (a target for prostate cancer) that bound with low micromolar affinity and were active in a cell-based assay. Moreover, I was involved in the discovery of 22 inhibitors of beta-secretase (an Alzheimer's target), again all of them active in at least one cell-based assay.
In my postdoctoral research with Brian Shoichet at the University of California, San Francisco, I investigate docking to the β2-adrenergic receptor. The key question was whether an unbiased docking screen against the recent X-ray structure can identify chemically novel binders for this target that has been so thoroughly investigated by ligand-based methods for over 50 years. Indeed, I found six highly potent ligands with Kis between 9 nM and 3.2 uM. Two of the compounds represent previously undescribed chemotypes and five are inverse agonists. The most potent compound is also the most effective inverse agonist ever described and has recently been crystallized, validating the computationally predicted binding mode.
In the wake of the numerous structural genomics projects, the structure -- but not the function -- of many enzymes is known. I use the High-Energy Intermediate (HEI) technique to identify substrates for enzymes of the amidohydrolase superfamily and have contributed to the elucidation of the substrate specificity and precise reaction mechanism of a lactonase of D. radiodurans, a dipeptidase of S. coelicolor and the first 8-oxoguanine deaminase ever described.
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Representative Publications :
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The hunt for 8-Oxoguanine Deaminase.
Richard S. Hall, Alexander A. Fedorov, Ricardo Marti-Arbona, Elena V. Fedorov, Peter Kolb, J. Michael Sauder, Stephen K. Burley, Brian K. Shoichet, Steven C. Almo and Frank M. Raushel
J. Am. Chem. Soc. 2010, 132, 1762-1763.
Docking screens: right for the right reasons?
Peter Kolb, and John J. Irwin
Curr. Top. Med. Chem. 2009, 9, 755-770. [review]
Structure-based discovery of β2-adrenergic receptor ligands.
Peter Kolb†, Daniel M. Rosenbaum†, John J. Irwin, Juan José Fung, Brian K. Kobilka*, and Brian K. Shoichet*
Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 6843-6848.
Structure-based tailoring of compound libraries for high-throughput screening: Discovery of novel EphB4 kinase inhibitors.
Peter Kolb, Catherine Berset Kipouros, Danzhi Huang, and Amedeo Caflisch
Proteins: Struct. Funct. Bioinf. 2008, 73, 11-18.
Discovery of kinase inhibitors by high-throughput docking and scoring based on a transferable linear interaction energy model.
Peter Kolb†, Danzhi Huang†, Fabian Dey†, and Amedeo Caflisch
J. Med. Chem. 2008, 51, 1179-1188.
Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking.
Peter Kolb*, and Amedeo Caflisch*
J. Med. Chem. 2006, 49, 7384-7392.
†these authors contributed equally. *co-corresponding authors.
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