2. Theory

There is a long history to bioisosteric replacement [1]. Most medicinal chemists are well versed in standard sets of bioisosteric fragments. Likewise, there is a long history of computational approaches to bioisosteres [2], [3]. There have been several attempts to examine sets of known active compounds to empirically identify bioisosteric fragments [4], [5]. While this is an interesting exercise, it has two drawbacks. First, it can only identify bioisosteric fragment pairs that are already known. While these provide interesting study, they are often familiar to experienced medicinal chemists and modelers. Second, it identifies many incidental rather than meaningful fragment pairs. These result from the fact that simply because two molecules bind to the same site does not mean they differ only by bioisosteric replacement. For instance, chemists may analog a compound by subsituting an N-methyl group with an N-benzyl group in order to identify new binding pockets. However, simply because both of these compounds are bioactive does not mean that methyl and benzyl are bioisosteres (though they would be identified as such by some methods). While one may apply various heuristics, such as size, to avoid this problem, we hope to explore methods that are more robust.

An alternative approach has been to generate an algorithm that would predict whether two fragments are bioisosteres. Several groups including Bartlett [2], Verloop [3] and Willet [6] have developed methods in this area. Here we seek to capitalize on and extend the ideas developed by these workers.

Subsections

				Brood: Fragment replacement for Medicinal Chemistry

				Brood: Fragment replacement for Medicinal Chemistry