Validation Study on an Information Driven Library Design Strategy

Abstract: A new method is introduced for performing reagent selection for chemical library designbased on topological (2D) pharmacophore fingerprints. Optimal reagent selection is achievedby optimising the Shannon entropy of the 2D pharmacophore distribution for the reagent set.The method, termed ProSAR, is therefore expected to enumerate compounds that could serveas a good starting point for deriving a structure activity relationship (SAR) in combinatoriallibrary design. The main goal for current study is to validate this methodology by applying iton several library design examples where the active compounds were already known andcomparing the performance of ProSAR libraries with random libraries and traditionaldiversity based libraries. The results show that ProSAR libraries generally have betterpharmacophore coverage than libraries coming from other design strategies. The effectivenessof generating active compounds for the designed library is also evaluated by first doing asimilarity search against GVKBio database with library compounds as query structures, thencomparing the number of retrieved active compounds for different libraries. The resultsdemonstrate that in most of cases, ProSAR libraries retrieve more active compounds thanother libraries. The ProSAR strategy is further expanded to include product property profilesfor aqueous solubility, hERG risk assessment etc. in the optimisation process so that thereagent pharmacophore diversity and the product property profile are optimisedsimultaneously via a genetic algorithm. The validation study results show that by using theProSAR methodology, the designed libraries can achieve good pharmacophore coverage andproduct property profile simultaneously.