Structure-based lead optimization discovery

Rajamani, R., Good, A.C. Ranking poses in structure-based lead discovery and optimization Current trends in scoring function development. Curr. Opin. Drug. Discov. Devel. 2007,10,308-15. 

Aldose reductase 2 DOCK [40]/MD (AMBER [72]) Single-structure-based docking Drug discovery/lead optimization Low pM [77]... 

L. H. Hall, L. B. Kier, and L. M. Hall, Topological QSAR applications Structure information representation in drug discovery, applications to drug discovery— Ligand-based lead optimization, in Comprehensive Medicinal Chemistry II, Vol. 4, D. J. Triggle and J. B. Taylor (Eds.), Elsevier, Oxford, UK, 2007, pp. 537-574. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

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