Combinatorial library-based design with Basis Products

Abstract

Uncovering useful lead compounds from a vast virtual library of synthesizable compounds continues to be of tremendous interest to pharmaceutical researchers. Here we present the concept of Basis Products (BPs), a new and broadly applicable method for achieving efficient selections from a combinatorial library. By definition, Basis Products are a strategically selected subset of compounds from a potentially very large combinatorial library, and any compound in a combinatorial library can represented by its BPs. In this article we will show how to use BP docking scores to find the top compounds of a combinatorial library. Compared with the brute-force docking of an entire virtual library, docking with BPs are much more efficient because of the substantial size reduction, saving both time and resources. We will also demonstrate how BPs can be used for property-based combinatorial library designs. Furthermore, BPs can also be considered as fragments carrying chemistry knowledge, hence they can potentially be used in combination with any fragment-based design method. Therefore, BPs can be used to integrate combinatorial design with structure-based design and/or fragment-based design. Other potential applications of BPs include lead hopping and consensus core building, which we will describe briefly as well in this report.