Recent reports of exceptionally numerous and accurate make-and-test potency forecasts from topomer CoMFA and a proposed causal explanation (1), coupled with the inherent simplicity, robustness, and speed of topomer methodologies generally, further encourage consideration of other new topomer-based tools for lead optimization. These tools include:�         R-group virtual screening: Searching such large structural databases as ZINC, using as query one or more topomer CoMFA QSAR models, for R-groups indicated as imparting one or more improved biological potencies (2).�         Quantitative Series Enrichment Analysis: Constructing training sets and generating 3D-QSARs by objective and automatic means, for example leveraging public SAR data to advance a project (3).�         AllChem: Generating and searching, in hours among >10E20 synthetically accessible and medicinally appropriate structures, for �lead-hops� or R groups having shape similarities and predicted potencies that address a project's multiple goals (4).�         Desktop Deployment: Applying 3D-QSAR models wherever and whenever most convenient and productive, for example at a project team meeting.�         Template-Constrained Fragment Alignment: Combining the virtues of the manual pharmacophoric/receptor-based approach with those afforded by topomers to yield a third general approach to structural alignments for 3D-QSAR,.   References:Cramer, R. D. J. Comp.-Aided Drug Design, 2011, 25, 197-201.Cramer, R. D.; Cruz, P.; Stahl, G.; Curtiss, W. C.; Campbell, B.; Masek, B. B.; Soltanshahi, F. J. Chem. Inf. Model. 2008, 48, 2180-2195Wendt, B.; Uhrig, U.; Boes, F.. J. Chem. Inf. Model. 2011, 51, accepted.Cramer, R. D.; Soltanshahi, F.; Jilek, R.; Campbell, B. J. Comp.-Aided Drug Design, 2007, 21, 341-350.

Topomers: A cornucopeia of novel and promising CADD methods, to help guide lead optimization?

242nd National Meeting (2011)

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