Lead discovery analysis

An alternative metric to describe 3-D properties of molecules is discussed by Ashton et al.26 In their approach, a pharmacophore fingerprint is used in conjunction with conformational searching to determine possible 3-D shapes that molecules can adopt. Tools from Tripos and CDL are available to carry out this type of analysis. However as with other methods there are limitations, the completeness of conformational searching being one. Perhaps the most important limitation of the approach is that it has a tendency to pick the most flexible molecules (that set the most pharmacophore bits). In a lead discovery experiment, following up on flexible molecules can be a long and sometimes fruitless process. 

Previously, inductive QSAR descriptors have been successfully applied to a number of molecular modeling studies, including quantification of antibacterial activity of organic compounds (89), calculation of partial charges in small molecules and proteins (81), and in comparative docking analysis as well as in in silico lead discovery (82). Inductive QSAR descriptors have been used... 

Statistical HTS data analysis and discovery cheminformatics are integral components of an HTS-driven lead discovery process. Various statistical and visualization techniques are routinely... 

Reynolds, C.H., Druker, R. and Pfahler, L.B. Lead Discovery Using Stochastic Cluster Analysis (SCA) A New Method for Clustering Structurally Similar Compounds. J. Client. Inf. Comput. Set, 1998,38,305-312. 

Lead Discovery Using Stochastic Cluster Analysis (SCA) A New Method for Clustering Structurally Similar Compounds. 

As the preparation of large libraries for lead discovery became routine, the burden placed on analysis techniques focused mainly on throughput and qual-ity. ° However, biological assay requirements typically required pure compounds. Thus, the focus shifted toward the use of automated high throughput purification methods applied to libraries of discrete compounds. Reverse-phase analytical and preparative HPLC formats in conjunction with MS techniques have been critical for the high throughput purification... 

Small-molecule libraries synthesized in the parallel format may be those directed toward either lead discovery or lead optimization, and may be synthesized either on a solid-support or in solution. The large numbers of discrete compounds generated by these parallel formats require analysis, and most frequently, purification. This chapter will illustrate how mass spectrometry assists these efforts. 

This analysis was designed specifically for large structurally diverse data sets resulting useful for lead discovery and drug design. The two basic assumptions in substructural analysis are (a) a weight (SAP index) for each substructure can be calculated, which characterizes its differential occurrence in active and inactive compounds [Cramer III, Redl et al, 1974] ... 

Design and Diversity Analysis of Compound Libraries for Lead Discovery... 

The following sections of this chapter describe the generic process of lead discovery and are followed by a more detailed analysis of some of the important functions involved in its execution. 

In this chapter, we will start by providing an overview of the evolution of the 3D pharmacophore concept and subsequently show the usefulness of 3D pharmacophore searching in modern lead discovery. The use of this approach for combinatorial library design, compound classification, and molecular diversity analysis is presented. Examples of successful applications reported in the last couple of years are reviewed. 

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