Leads discovery

The lead discovery process is depicted in Figure 10.4-4 and shows how the different methods are interconnected. A lead structure can be discovered by serendipity. In rational drug design all information available about a target serves to direct... 

The entire domain of "new-lead" discovery has expanded considerably. This development has affected what have traditionally been divergent approaches, namely QSAR and stmcture-based design, leading them to become integrated so as to provide a more powerful approach (135). Several recently pubHshed comprehensive volumes capture the state of the art and can be consulted to determine precedents relevant to any particular study (134-137). 

Cavallaro CL, Schnur DM, Tebben AJ. Molecular diversity in lead discovery From quantity to quality. In Oprea Tl, editor, Chemoinformatics in drug discovery, Weinheim, Wiley-VCH, 2004 175-98. 

Wilton DJ, Willett P, Mullier G, Lawson K. Comparison of ranking methods for virtual screening in lead-discovery programmes. J Chem Inf Comput Sci 2003 43 469-74. 

Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H. Fragment based lead discovery using x-ray crystallography, J Med Chem 2005 48 403-13. 

Pharmaceutical lead discovery and optimization have historically followed a sequential process in which relatively small sets of individual compounds are... 

Oprea TI. Chemical space navigation in lead discovery. Curr Opin Chem Biol 2002 6 384-9. 

Murray CW, Clark DE, Auton TR, Firth MA, Li J, Sykes RA, Waszkowycz B, Westhead DR, Young SC. PRO SELECT combining structure-based drug design and combinatorial chemistry for rapid lead discovery. J Comput Aided Mol Des 1997 11 193-207. 

Winkler DA. Neural networks as robust tools in drug lead discovery and development. Mol Biotechnol 2004 27 139-68. 

Oprea TI. Current trends in lead discovery are we looking for the appropriate properties / Comput Aided Mol Des 2002 16 325-34. 

Toyoda T, Brobey RKB, Sano G, Horii T, Tomioka N, Itai Akiko. Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Biochem Biophys Res Commun 1997 235 515-19. 

C. W., Rees, D. G. Eragment-based lead discovery leads by design. Drug Discov. Today 2005, 10, 987-992. 

C. W., Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discov. 2004,... 

Congreve, M., Carr, R., Murray, C., Jhoti, H. A rule of three for fragment-based lead discovery Drug Discov. Today 2003, 8, 876-877. 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

Keywords VS, Virtual Screening, Lead discovery, lead, HTS, Pharmacophore-Based, Structure-Based, Fragment-based, Ligand-based, Docking, Scoring, hybrid workflows, VS strategy, Benchmarking VS... 

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