Lead discovery molecular diversity

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. 

Molecular Diversity in Lead Discovery From Quantity to Quality... 

Schuffenhauer A, Popov M, Schopfer U, et al. (2004) Molecular diversity management strategies for building diverse and focused lead discovery compound screening collections. Comb. Chem. High Throughput Screen. 7 771-781. 

In recent years, combinatorial synthesis has rapidly emerged as a powerful methodology for the preparation of a wide variety of diverse molecular structures. The generation of non-oligomeric, small-molecule libraries has especially attracted great attention for new drug lead discovery and optimization due to their preferable physiochemical and pharmacokinetic properties . 

Parlow, J. J. Normansell, J. E. Discovery of a Herbicidal Lead Using Polymer-Bound Activated Esters in Generating a Combinatorial Library of Amides and Esters, Molecular Diversity, 1996, /, 217. 

Natural products represent an unparalleled source of molecular diversity for innovative drug discovery. In the pharmaceutical industry, there is an urgent need to identify novel lead structures for effective drug development in many therapeutic areas. It is likely that natural halogen compounds will continue to contribute leads to future research. 

Synthesized libraries of compounds such as Optiverse are not the only source of new leads. Natural products also play an important role in lead discovery. There are numerous examples where natural products have led to the discovery of new drugs. It is also clear that they represent an inexpensive source of nature s molecular diversity in a lead discovery program. However, a key limitation that must be overcome if leads are to be developed into drugs is they are usually difficult to synthesize, thereby making it more resource-intensive to generate related compounds with better properties. 

Martin, J.F., presentation in IBC s Molecular Diversity and Combinatorial Chemistry - Applications for Drug Lead Discovery, San Diego, CA, U.S.A., 1996. 

As already stated, the spectrum of reaction types, which have been successfully adapted to the solid-phase format, has expanded noticeably over the last few years. The examples listed above illustrate the fact that a remarkable toolbox is now available to the organic chemist, whose challenge is to creatively combine reactions to powerful modular approaches with broad validity for whole sets of building blocks. Achievements in this area will pave the way toward molecular diversity for lead discovery, as well as efficient analoging of target structures. 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

Ashton, M.J., Jaye, M.C. and Mason, J.S. New Perspectives in Lead Generation II Evaluating Molecular Diversity. Drug Discovery Today, 1996,1,71-78. 

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