Molecular biology lead compounds

This chapter lists some representative examples of biochemicals and their origins, a brief indication of key techniques used in their purification, and literature references where further details may be found. Simpler low molecular weight compounds, particularly those that may have been prepared by chemical syntheses, e.g. acetic acid, glycine, will be found in Chapter 4. Only a small number of enzymes and proteins are included because of space limitations. The purification of some of the ones that have been included has been described only briefly. The reader is referred to comprehensive texts such as the Methods Enzymol (Academic Press) series which currently runs to more than 344 volumes and The Enzymes (3rd Edn, Academic Press) which runs to 22 volumes for methods of preparation and purification of proteins and enzymes. Leading referenees on proteins will be found in Advances in Protein Chemistry (59 volumes. Academic Press) and on enzymes will be found in Advances in Enzymology (72 volumes, then became Advances in Enzymology and Related Area of Molecular Biology, J Wiley Sons). The Annual Review of Biochemistry (Annual Review Inc. Patio Alto California) also is an excellent source of key references to the up-to-date information on known and new natural compounds, from small molecules, e.g. enzyme cofactors to proteins and nucleic acids. 

Objectives Optimize biological activity of drugs Find new active lead compounds Characteristics Response in isolated systems Effects are specific and well defined Specific mechanism of action Receptor is known in most cases Techniques Hansch Approach Multivariate Analysis Computerized molecular modeling Estimate rates of fate processes Analyze Processes Whole organism response Net effects (mortality growth, etc.) Specific nonspecific mechanisms Receptor unknown in most cases Hansch Approach Multivariate Analysis Molecular modeling not applied... 

Jacoby E, Schuffenhauer A, Addin P. (2004) The contribution of molecular informatics to chemogenomics. Knowledge-based discovery of biological targets and chemical lead compounds. In H Kubini, G Muller (eds), Chemogenomics in Drug Discovery — A Medicinal Chemistry Perspective, pp. 139-166. Wiley-VCH,Weinheim. 

Arrays of biological data can form the basis for uniquely informative molecular descriptors. By defining the relationships between compounds using biological descriptors (in vitro profiles) in addition to chemical structures, medicinal chemists are given new perspectives to support lead optimization. 

In summary, based on the observation of divergent in vitro and in vivo SAR, a new class of cholesterol-lowering compounds was discovered. Subsequent biological characterization of the first generation lead compound SCH-48461, limited the site of action to be at or near the intestinal villi, with the most probable mechanism being the inhibition of luminal absorption. An SAR optimization based solely on an in vivo assay and without biochemical characterization of the molecular target led to the design of ezetimibe (1). 

---