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HierVLS Hierarchical Docking Protocol for Virtual Ligand Screening of Large-Molecule Databases

Floriano, Wely B. and Vaidehi, Nagarajan and Zamanakos, Georgios and Goddard, William A., III (2004) HierVLS Hierarchical Docking Protocol for Virtual Ligand Screening of Large-Molecule Databases. Journal of Medicinal Chemistry, 47 (1). pp. 56-71. ISSN 0022-2623. doi:10.1021/jm030271v.

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To provide practical means for rapidly scanning the extensive experimental combinatorial chemistry libraries now available for high-throughput screening (HTS), it is essential to establish computational virtual ligand screening (VLS) techniques to rapidly identify out of a large library all active compounds against a particular protein target. Toward this goal we developed HierVLS, a fast hierarchical docking approach that starts with a coarse grain conformational search over a large number of configurations filtered with a fast but crude energy function, followed by a succession of finer grain levels, using successively more accurate but more expensive descriptions of the ligand−protein−solvent interactions to filter successively fewer cases. The final step of this procedure optimizes one configuration of the ligand in the protein site using our most accurate energy expression and description of the solvent, which would be impractical for all conformations and sites sampled in the coarse level. HierVLS is based on the HierDock approach, but rather than allowing an hour or more to determine the best binding site and energy for each ligands (as in HierDock), we have adapted our procedure so that it can lead to reliable results while using only 4 min (866 MHz Pentium III processor) per ligand. To validate the accuracy for HierVLS to predict the experimentally observed binding conformation, we considered 37 cocrystal structures comprising 11 target proteins. We find that HierVLS identifies the correct binding mode for all 37 cocrystals. In addition, the calculated binding energies correlate well with available experimental binding constants. To validate how well HierVLS can identify the correct ligand in an extensive library of decoys, we considered a library of over 10 000 molecules. HierVLS identifies 26 out of the 37 cases in the top 2% ranked by binding affinity among the 10 037 molecules. The failures result from either metal-containing sites on the protein or water-mediated ligand−protein interactions, which we anticipate can be solved within the constraints of practical VLS. We then applied HierVLS to screen a 55000-compound virtual library against the target protein−tyrosine phosphatase 1B (ptp1b). The top 250 compounds by binding affinity included all six ptp1b cocrystal ligands added to the library plus three other experimentally confirmed binders. The best (top 1) binder is an experimentally confirmed positive. We conclude that HierVLS is useful for selecting leads for a particular target out of large combinatorial databases.

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Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2004 American Chemical Society. Received June 9, 2003; Publication Date (Web): November 26, 2003. This project started as a challenge from Prof. Peter Schultz of Scripps Research Institute. We thank Mr. Sheng Ding, Dr. B. D. Bursulaya, and Dr. Schultz for helpful discussions. We thank Prof. Schultz and the GNF for use of their computer facilities for carrying out many of the calculations. In addition, we thank Dr. B. D. Bursulaya and Prof. Charles Brooks for permission to report some of their results prior to publication. This research was supported partially by Grants NIH-BRGRO1-GM625523, NIH-R29AI40567, and NIH-HD36385, and the computational facilities were provided by an SUR grant from IBM and a DURIP grant from ARO. The facilities of the Materials and Process Simulation Center are also supported by DURIP-ONR, DOE (ASCI ASAP), NSF, MURI-ARO, MURI-ONR, General Motors, ChevronTexaco, Seiko-Epson, Beckman Institute, and Asahi Kasei.
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Army Research Office (ARO)UNSPECIFIED
Office of Naval Research (ONR)UNSPECIFIED
Department of Energy (DOE)UNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
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Official Citation:HierVLS Hierarchical Docking Protocol for Virtual Ligand Screening of Large-Molecule Databases Wely B. Floriano, Nagarajan Vaidehi, Georgios Zamanakos, and William A. Goddard, III Journal of Medicinal Chemistry 2004 47 (1), 56-71 DOI: 10.1021/jm030271v
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76678
Deposited By: Tony Diaz
Deposited On:19 Apr 2017 17:47
Last Modified:15 Nov 2021 17:01

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