The NEWLEAD program: a new method for the design of candidate structures from pharmacophoric hypotheses

Abstract

We have developed a computer program, called NEWLEAD, for the automatic generation of candidate structures conforming to the requirements of a given pharmacophore. The treatment consists in connecting the pharmacophoric pieces with spacers assembled from small chemical entities (atoms, chains, or ring moieties). We have tested the program on several sets of input fragments, each comprising selected functional groups obtained from the bioactive conformations of reference molecules. In addition to the expected solutions, the program can generate new structures that are chemically unrelated to the reference molecules. This provides an unbiased starting point for the design of new generations of lead structures. The concept used in this approach is presented and discussed. The present possibilities of the program are illustrated by some examples. The treatment is very fast, because only a few bonds are created between building blocks already having ideal geometries. The ability to generate rapidly a variety of molecules conforming to a three-dimensional pharmacophoric model makes NEWLEAD a useful tool with wide applicability in rational drug design, including the areas of molecular mimicry and peptidomimetism.