The measurement of molecular diversity: a three-dimensional approach.
This paper describes a method for selecting a small, highly diverse subset from a large pool of molecules. The method has been employed in the design of combinatorial synthetic libraries for use in high-throughput screening for pharmaceutical lead generation. It computes diversity in terms of the main factors relevant to ligand-protein binding, namely the three-dimensional arrangement of steric bulk and of polar functionalities and molecular entropy. The method was used to select a set of 20 carboxylates suitable for use as side-chain precursors in a polyamine-based library. The method depends on estimates of various physical-chemical parameters involved in ligand-protein binding; experiments examined the sensitivity of the method to these parameters. This paper compares the diversity of randomly and rationally selected side-chain sets; the results suggest that careful design of synthetic combinatorial libraries may increase their effectiveness several-fold.
Chapman
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Afferent Systems Inc., San Francisco, CA 94114, USA.
D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019277:Entropy; D005069:Evaluation Studies as Topic; D008024:Ligands; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry
D000596:Amino Acids; D002264:Carboxylic Acids; D008024:Ligands; D011073:Polyamines