Topomer CoMFA: a design methodology for rapid lead optimization.
To provide an objective QSAR methodology that might accelerate lead optimization, the CoMFA and topomer technologies have been merged, with surprisingly good results. A series of input structures are each broken into two or more fragments at central acyclic single bonds, while removing any core fragment structurally common to the entire series. Standard topomer 3D models are automatically constructed for each fragment, and a set of steric and electrostatic fields ("CoMFA column") is generated for each set of topomers. Application of "topomer CoMFA" to 15 3D-QSAR analyses taken from the literature (847 structures) were all successful, with an average q(2) of 0.520 (literature average q(2) = 0.636) and an average standard deviation of true prediction (SDEP) of 0.688 (literature average SDEP = 0.553) for 133 structures. Topomer CoMFA results are particularly promising as queries into virtual libraries already composed of topomer structures, to directly seek structures having increased potency. Accordingly, in 13 of the 15 such "topomer CoMFA searches" attempted, combinations of commercially offered fragments were retrieved that were predicted to be more potent than any structure described in the original publication (average predicted potency increase = 20 x), showing in principle how optimization could occur.
Cramer
Richard D
RD
Tripos Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA. cramer@tripos.com
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D003374:Coumarins / Q000737:chemistry; D018492:Dopamine Antagonists / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D058906:Purinergic P1 Receptor Agonists; D011724:Pyridazines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000737:chemistry; D011963:Receptors, GABA-A / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry
D003374:Coumarins; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D009842:Oligopeptides; D010879:Piperazines; D058906:Purinergic P1 Receptor Agonists; D011724:Pyridazines; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011963:Receptors, GABA-A; D013449:Sulfonamides; D010649:Phenylalanine; D000241:Adenosine