The measurement of molecular diversity: A three-dimensional approach
- 1 December 1996
- journal article
- research article
- Published by Springer Nature in Journal of Computer-Aided Molecular Design
- Vol. 10 (6) , 501-512
- https://doi.org/10.1007/bf00134174
Abstract
Summary 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.Keywords
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