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| Osman F. Güner, Turquoise Consulting |
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Dr. Osman F. Güner is the founder of Turquoise Consulting, providing consulting and training services in the CADD software area. During 1996-2005, he was with Accelrys Inc. in various positions with his latest responsibility as the Executive Director of Cheminformatics and Rational Drug Design with overall profit and loss responsibilities for Accelrys’ cheminformatics and small molecule modeling software products. Prior to joining Accelrys, Dr. Güner was a Senior Scientist and ISIS/Host Product Manager for MDL Information Systems, Inc. (MDL) during 1989-96 where he managed MDL’s various information management programs.
He was a post-doctoral fellow at the University of Alabama at Birmingham from 1987 - 1989, where worked in theoretical studies and design of small, high energy/density materials to be used as rocket propellants. Dr. Güner earned a Ph.D. in physical organic chemistry from Virginia Commonwealth University, in December 1986, where he was a Mary E. Kapp-Research Assistant. He earned an M.S. in organic chemistry and a B.S in chemistry from Middle East Technical University in Ankara, Turkey in 1981, and in 1979, respectively.
Dr. Güner has published over 35 papers and book chapters, and over 75 abstracts. He is a member of the American Chemical Society, International QSAR and Modelling Society, and a fellow of the American Institute of Chemists. He is currently serving as the Chair at the ACS Chemical Information Division (2006), as Board of Directors of the International QSAR and Modelling Society (2006-2010), and a Trustee of Chemical Structure Association Trust (2006-2008).
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Advanced Techniques in Pharmacophore Perception and Successful Applications in Drug Design
Osman F. Güner, Turquoise Consulting
Pharmacophore perception and use of pharmacophores in drug discovery and design has evolved from a specialist activity in early 90s into an essential aspect of modern computer-aided drug design. The significance of pharmacophore technology has been continuously increasing together with the increasing availability of protein targets. In this workshop we will briefly cover the historical evolution of the pharmacophore concept and its successful use and application in drug discovery.
The bulk of the lecture focuses on various techniques for pharmacophore modeling and database searching. Methods for perceiving a pharmacophore are presented, starting from the simplest method of visual pattern recognition. The significance of training set selection is covered with an example for PDE IV inhibitors. Techniques for pharmacophore model refinement are then presented for 5-HT3 inhibitors, and finally predictive model development is covered with two examples: FTP inhibitors and antimalarial agents.
The second half of the workshop starts with a review of hit list and pharmacophore analysis metrics. It then provides details for various three-dimensional database-searching techniques. Vector-based queries are exemplified with an application to HIV-1 protease inhibitors and endothelin antagonists. Methotrexate bound conformation within DHFR is used to demonstrate the utility of ligand-shape in 3D searching, as well as combined shape and pharmacophore search. This section ends with a discussion of the conformational flexibility issue in 3D databases and provides a comparison of current solutions.
The availability of new targets and protein structures is now generating a renewed interest in structure-based drug design. In a similar fashion, there is now more interest in the development of receptor-based pharmacophores, as opposed to the traditional ways of using a set of known active molecules to derive a putative pharmacophore. Development of pharmacophore models entirely from the receptor active site provides new challenges. Typically, an active site will have more potential binding sites than the ones that are utilized by a given set of active compounds. Hence, automated pharmacophore model generation from receptor active sites becomes a combinatorial problem and the hundreds to thousands of pharmacophore models that are generated in this manner need to be evaluated and scored. We will discuss these problems and propose solutions based on some recent work. The workshop will close with several examples from literature and success stories.
Further reading:
1. Güner OF: The impact of pharmacophore modeling in drug design. IDrugs (2005) 8(7):567-572.
2. Van Drie J: Pharmacophore-based virtual screening: A practical perspective, In Virtual Screening in Drug Discovery. Alvarez J, Shoichet B (Eds), CRC Press, Boca Raton, FL, USA (2005):157-205.
3. Güner OF: History and evolution of the pharmacophore concept in computer-aided drug design. Curr Top Med Chem (2002) 2(12):1321-1332.
4. Mason JS, Good AC, Martin EJ: 3D pharmacophores in drug discovery. Curr Pharm Design (2001) 7(7):567-597.
5. Güner, OF (ed): Pharmacophore Perception, Development, and Use in Drug Design. IUL Biotechnology Series, La Jolla, California, USA (2000).
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