Novel lead structures

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. 

This first section focuses on three major areas library generation method (mixtures and single compounds) chemistry (solid-phase and solution synthesis) and quality/speed (analytical and automation). Finally, the section ends with a chapter reviewing examples where combinatorial chemistry/rapid organic synthesis has been used for discovering novel lead structures for pharmaceutical purposes. 

Rebek and co-workers [5-8] prepared a series of libraries based around two central rigid cores 9,9-dimethylxanthene and cubane tetracid chlorides. Unlike the above approaches, a series of iterative sublibrary generation and screening was used to identify increasingly potent compounds. All the above approaches identified novel lead structures of potential biological interest. 

Peptidomimetic modifications of the tet-rapeptide sequence have led to the conforma-tionally constrained compound (69)as a selective inhibitor of caspase-1 or interleukin-1 converting enzyme (ICE) as potential anti-inflammatory compounds (131). Recently, new non-peptide peptidomimetic diphenyl ether sulfonamides have been described as novel lead structures (70) (Fig. 15.32) (132). 

MARINE ORGANISMS AS A SOURCE OF NOVEL LEAD STRUCTURES FOR DRUG DEVELOPMENT... 

These examples show how the combinatorial peptoid approach holds enormous potential for the discovery of novel lead structures for drug development. In this context a postmodification on solid-phase of peptoid side chains, bearing alkene and alkyne moieties, via [3 + 2] cyclo-addition of nitrile oxides, enhances further the molecular diversity and the possibility to find new therapeutic agents [11]. Moreover, polymers of N-substituted glycines containing chiral side chains display interesting conformational preferences [12]. NMR and CD data indicate that the major species adopts in methanol a stable right-handed helical structure with o. v-amidc bonds. 

De novo structure-based design of novel lead structures... 

Fig, 26.19 Structure-based design of thymidylate synthase inhibitors de novo design of a novel lead structure. See text for explanation. 

Pharmacophore-based screening is a virtual screening (VS) method used to automatically evaluate millions of compounds by computer programs [16]. A variety of applications for VS exist. It can be applied to obtain novel lead structures from corporate or commercial databases in early drug discovery, to search virtual... 

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