5720 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 18 (10) Cho, Y.; Ioerger, T. R.; Sacchettini, J. C. Discovery of novel nitrobenzothiazole inhibitors for Mycobacterium tuberculosis ATP phosphoribosyl transferase (HisG) through virtual screening. J. Med. Chem. 2008, 51, 5984–5992. (11) Kiss, R.; Kiss, B.; Konczol, A.; Szalai, F.; Jelinek, I.; Laszlo, V.; Noszal, B.; Falus, A.; Keseru, G. M. Discovery of novel human histamine H4 receptor ligands by large-scale structure-based vir- tual screening. J. Med. Chem. 2008, 51, 3145–3153. (12) Cavasotto, C. N.; Orry, A. J.; Murgolo, N. J.; Czarniecki, M. F.; Kocsi, S. A.; Hawes, B. E.; O’Neill, K. A.; Hine, H.; Burton, M. S.; Voigt, J. H.; Abagyan, R. A.; Bayne, M. L.; Monsma, F. J., Jr. Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J. Med. Chem. 2008, 51, 581–588. (13) Eswar, N.; John, B.; Mirkovic, N.; Fiser, A.; Ilyin, V. A.; Pieper, U.; Stuart, A. C.; Marti-Renom, M. A.; Madhusudhan, M. S.; Yerkovich, B.; Sali, A. Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 2003, 31, 3375–3380. (14) Altschul, S. F.; Gish, W.; Miller, W.; Myers, E. W.; Lipman, D. J. Basic local alignment search tool. J. Mol. Biol. 1990, 215, 403–410. (15) Moustakas, D. T.; Lang, P. T.; Pegg, S.; Pettersen, E.; Kuntz, I. D.; Brooijmans, N.; Rizzo, R. C. Development and validation of a modular, extensible docking program: DOCK 5. J. Comput.-Aided Mol. Des. 2006, 20, 601–619. (16) Nissink, J. W.; Murray, C.; Hartshorn, M.; Verdonk, M. L.; Cole, J. C.; Taylor, R. A new test set for validating predictions of protein-ligand interaction. Proteins 2002, 49, 457–471. (17) Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol. 1997, 267, 727–748. (18) Verdonk, M. L.; Berdini, V.; Hartshorn, M. J.; Mooij, W. T.; Murray, C. W.; Taylor, R. D.; Watson, P. Virtual screening using protein-ligand docking: avoiding artificial enrichment. J. Chem. Inf. Comput. Sci. 2004, 44, 793–806. (19) Kellenberger, E.; Rodrigo, J.; Muller, P.; Rognan, D. Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins 2004, 57, 225–242. (20) Perola, E.; Walters, W. P.; Charifson, P. S. A detailed comparison of current docking and scoring methods on systems of pharmaceu- tical relevance. Proteins 2004, 56, 235–249. (21) Ferrara, P.; Gohlke, H.; Price, D. J.; Klebe, G.; Brooks, C. L., III. Assessing scoring functions for protein-ligand interactions. J. Med. Chem. 2004, 47, 3032–3047. (22) Kontoyianni, M.; McClellan, L. M.; Sokol, G. S. Evaluation of docking performance: comparative data on docking algorithms. J. Med. Chem. 2004, 47, 558–565. (23) Wang, R.; Lu, Y.; Fang, X.; Wang, S. An extensive test of 14 scoring functions using the PDBbind refined set of 800 pro- tein-ligand complexes. J. Chem. Inf. Comput. Sci. 2004, 44, 2114–2125. (24) Xing, L.; Hodgkin, E.; Liu, Q.; Sedlock, D. Evaluation and application of multiple scoring functions for a virtual screening experiment. J. Comput.-Aided Mol. Des. 2004, 18, 333–344. (25) Onodera, K.; Satou, K.; Hirota, H. Evaluations of molecular docking programs for virtual screening. J. Chem. Inf. Model. 2007, 47, 1609–1618. (26) Zhou, Z.; Felts, A. K.; Friesner, R. A.; Levy, R. M. Comparative performance of several flexible docking programs and scoring functions: enrichment studies for a diverse set of pharmaceutically relevant targets. J. Chem. Inf. Model. 2007, 47, 1599–1608. (27) Huang, N.; Shoichet, B. K.; Irwin, J. J. Benchmarking sets for molecular docking. J. Med. Chem. 2006, 49, 6789–6801. (28) Lorber, D. M.; Shoichet, B. K. Flexible ligand docking using conformational ensembles. Protein Sci. 1998, 7, 938–950. (29) Lorber, D. M.; Shoichet, B. K. Hierarchical docking of databases of multiple ligand conformations. Curr. Top. Med. Chem. 2005, 5, 739–749. (30) Tong, W.; Wei, Y.; Murga, L. F.; Ondrechen, M. J.; Williams, R. J. Partial order optimum likelihood (POOL): maximum like- lihood prediction of protein active site residues using 3D Struc- ture and sequence properties. PLoS Comput. Biol. 2009, 5, e1000266. Irwin et al. (31) Weisel, M.; Proschak, E.; Kriegl, J. M.; Schneider, G. Form follows function: shape analysis of protein cavities for receptor-based drug design. Proteomics 2009, 9, 451–459. (32) Laurie, A. T.; Jackson, R. M. Methods for the prediction of protein-ligand binding sites for structure-based drug design and virtual ligand screening. Curr. Protein Pept. Sci. 2006, 7, 395–406. (33) Pearlman, D. A.; Case, D. A.; Caldwell, J. W.; Ross, W. S.; Cheatham, T. E., III; Debolt, S.; Ferguson, D.; Seibel, G.; Kollman, P. AMBER, a package of computer programs for applying mole- cular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules . Comput. Phys. Commun. 1995, 91, 1–41. (34) Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol. 1982, 161, 269–288. (35) Meng, E. C.; Shoichet, B. K.; Kuntz, I. D. Automated docking with grid-based energy evaluation. J. Comput. Chem. 1992, 13, 505–524. (36) Nicholls, A.; Honig, B. A Rapid Finite-Difference Algorithm, Utilizing Successive Over-Relaxation to Solve the Poisson- Boltzmann Equation. J. Comput. Chem. 1991, 12, 435–445. (37) Shoichet, B. K.; Mysinger, M. M. unpublished results, 2008. (38) OpenEye OEChem 1.6.1; OpenEye Scientific Software: Santa Fe, NM; www.eyesopen.com. (39) Irwin, J. J.; Shoichet, B. K. ZINC;a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model. 2005, 45, 177–182. (40) Mysinger, M. M. Unpublished automation and refinement of the DUD protocol, 2009. (41) Powers, R. A.; Morandi, F.; Shoichet, B. K. Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lacta- mase. Structure (Cambridge, MA, U.S.) 2002, 10, 1013–1023. (42) Doman, T. N.; McGovern, S. L.; Witherbee, B. J.; Kasten, T. P.; Kurumbail, R.; Stallings, W. C.; Connolly, D. T.; Shoichet, B. K. Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B. J. Med. Chem. 2002, 45, 2213–2221. (43) Babaoglu, K.; Simeonov, A.; Irwin, J. J.; Nelson, M. E.; Feng, B.; Thomas, C. J.; Cancian, L.; Costi, M. P.; Maltby, D. A.; Jadhav, A.; Inglese, J.; Austin, C. P.; Shoichet, B. K. A Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens Against β-Lactamase. J. Med. Chem. 2008, 51, 2502–2511. (44) Kolb, P.; Rosenbaum, D. M.; Irwin, J. J.; Fung, J. J.; Kobilka, B. K.; Shoichet, B. K. Structure-based discovery of {beta}2-adrenergic receptor ligands. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 6843–6848. (45) Delano, W. The PyMol Molecular Graphics System. (46) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera;a visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605–1612. (47) Gezelter, D. Jmol: an open-source Java viewer for chemical struc- tures in 3D. http://www.jmol.org. (48) Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucl. Acid. Res. 2000, 28, 235–242. (49) Henrick, K.; Feng, Z.; Bluhm, W. F.; Dimitropoulos, D.; Doreleijers, J. F.; Dutta, S.; Flippen-Anderson, J. L.; Ionides, J.; Kamada, C.; Krissinel, E.; Lawson, C. L.; Markley, J. L.; Nakamura, H.; Newman, R.; Shimizu, Y.; Swaminathan, J.; Velankar, S.; Ory, J.; Ulrich, E. L.; Vranken, W.; Westbrook, J.; Yamashita, R.; Yang, H.; Young, J.; Yousufuddin, M.; Berman, H. M. Remediation of the protein data bank archive. Nucleic Acids Res. 2008, 36, D426–433. (50) Huang, N.; Shoichet, B. K. Exploiting ordered waters in molecular docking. J. Med. Chem. 2008, 51, 4862–4865. (51) Yusuf, D.; Davis, A. M.; Kleywegt, G. J.; Schmitt, S. An alter- native method for the evaluation of docking performance: RSR vs RMSD. J. Chem. Inf. Model. 2008, 48, 1411–1422. (52) Irwin, J. J. Community benchmarks for virtual screening. J. Comput.-Aided Mol. Des. 2008, 22, 193–199. (53) Mysinger, M. M. Adjusted LogAUC - the aggregate percentage area between the ROC curve and random curve when plotted on a log scale from 0.1 to 100% . (54) Graves, A. P.; Brenk, R.; Shoichet, B. K. Decoys for docking. J. Med. Chem. 2005, 48, 3714–3728.