Combinatorial chemistry and library design have been reconciled by applying simple medicinal chemistry concepts to virtual library design. The herein reported "Scaffold-Linker-Functional Group" (SLF) approach has the aim to maximize diversity while minimizing the size of a scaffold-focused library with the aid of simple molecular variations in order to identify critical pharmacophoric elements. Straightforward rules define the way of assembling three building blocks: a conserved scaffold, a variable linker, and a variable functional group. By carefully selecting a limited number of functional groups not overlapping in pharmacophoric space, the size of the library is kept to a few hundred. As an application of the SLF approach, a small-sized combinatorial library (320 compounds) was derived from the scaffold of the known phosphodiesterase 4 inhibitor zardaverine. The most interesting analogues were further prioritized for synthesis and enzyme inhibition by FlexX docking to the X-ray structure of the enzyme, leading to a 900-fold increased affinity within nine synthesized compounds and a single screening round.
The results reported in this study will advance our understanding of the influence of the distinct chemical structures of inhibitors at the active site and aid the development of new virtual screening protocols to design novel AChE multi-target inhibitors.
This provides a better insight into the mode of interaction of various cruzain inhibitors, which show IC50 values in the nanomolar range but which do not interact with the triad. These findings can help researchers to find new cruzain inhibitors for use in the fight against the Chagas disease.
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