Can we use docking and scoring for hit-to-lead optimization?
- 393 Downloads
Docking and scoring is currently one of the tools used for hit finding and hit-to-lead optimization when structural information about the target is known. Docking scores have been found useful for optimizing ligand binding to reproduce experimentally observed binding modes. The question is, can docking and scoring be used reliably for hit-to-lead optimization? To illustrate the challenges of scoring for hit-to-lead optimization, the relationship of docking scores with experimentally determined IC50 values measured in-house were tested. The influences of the particular target, crystal structure, and the precision of the scoring function on the ability to differentiate between actives and inactives were analyzed by calculating the area under the curve of receiver operator characteristic curves for docking scores. It was found that for the test sets considered, MW and sometimes ClogP were as useful as GlideScores and no significant difference was observed between SP and XP scores for differentiating between actives and inactives. Interpretation by an expert is still required to successfully utilize docking and scoring in hit-to-lead optimization.
KeywordsDocking and scoring Glide Hit optimization ROC analysis Kinase KDR CDK2 ABL
The authors thank Robert Pearlstein, Richard Lewis, and Hanneke Jansen for their reviews of the manuscript.
- 3.Muegge I, Rarey M (2001) In: Boyd DB, Lipkowitz KB (eds) Reviews in computational chemistry, vol 17. Wiley-VCH, New York, Ch 1, p 1Google Scholar
- 4.Muegge I, Enyedy I (2003) In: Abraham D (ed) Burger’s medicinal chemistry 5th edn. vol 1. Wiley, New York, p 243Google Scholar
- 5.Muegge I, Enyedy I (2004) In: Bultinck P, De Winter H, Langenaeker W, Tollenaere J (eds) Computational medicinal chemistry for drug discovery. Marcel Dekker Inc, New York, p 405Google Scholar
- 10.Stouten PFW, Kroemer RT (2006) Comprehensive Medicinal Chemistry II 4:255Google Scholar
- 30.Hodous BL, Geuns-Meyer SD, Hughes PE, Albrecht BK, Bellon S, Bready J, Caenepeel S, Cee VJ, Chaffee SC, Coxon A, Emery M, Fretland J, Gallant P, Gu Y, Hoffman D, Johnson RE, Kendall R, Kim JL, Long AM, Morrison M, Olivieri PR, Patel VF, Polverino A, Rose P, Tempest P, Wang L, Whittington DA, Zhao H (2007) J Med Chem 50:611CrossRefGoogle Scholar
- 33.Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J (2002) Cancer Res 62:4236Google Scholar
- 36.Maestro, version 8.0.110, (2007) Schrodinger LLC, New YorkGoogle Scholar
- 37.LigPrep, version 1.2, (2007) Schrodinger LLC, New YorkGoogle Scholar
- 38.MacroModel, version 9.5.213, (2007) Schrodinger LLC, New YorkGoogle Scholar
- 45.Hanley JA, McNeil BJ (1982) Radiology 143:29Google Scholar