New Computational Approaches for NMR-based Drug Design: A Protocol for Ligand Docking to Flexible Target Sites
- Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York NY 10028 (United States)
NMR-based drug design has met with some success in the last decade, as illustrated in numerous instances by Fesik's ''ligand screening by NMR'' approach. Ongoing efforts to generalize this success have led us to the development of a new paradigm in which quantitative computational approaches are being integrated with NMR derived data and biological assays. The key component of this work is the inclusion of the intrinsic dynamic quality of NMR structures in theoretical models and its use in docking. A new computational protocol is introduced here, designed to dock small molecule ligands to flexible proteins derived from NMR structures. The algorithm makes use of a combination of simulated annealing monte carlo simulations (SA/MC) and a mean field potential informed by the NMR data. The new protocol is illustrated in the context of an ongoing project aimed at developing new selective inhibitors for the PCAF bromodomains that interact with HIV Tat.
- OSTI ID:
- 20888116
- Journal Information:
- AIP Conference Proceedings, Vol. 851, Issue 1; Conference: BIFI 2006 II international congress: From physics to biology- The interface between experiment and computation, Zaragoza (Spain), 8-11 Feb 2006; Other Information: DOI: 10.1063/1.2345634; (c) 2006 American Institute of Physics; Country of input: International Atomic Energy Agency (IAEA); ISSN 0094-243X
- Country of Publication:
- United States
- Language:
- English
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