Screening virtual libraries can be very useful in the hit and lead generation if high resolution structural target information is accessible. However, for the general use of virtual in drug discovery, several issues have to be solved: 1) academic groups mostly rely on the ZINC database to perform virtual screening exercises. Although freely accessible and compounds commercially available, its chemical diversity is rather limited as its size is; 2) virtual screening is predicting hits often with high rate of false positives. In case of ZINC approach purchasing compounds then can become quite expensive. In case of a de novo synthesis approach a lot of expensive synthesis time can be wasted. Thus we have introduced the pharmacophore screening approach ANCHOR.QUERY, which can screen very large libraries of virtual compounds for receptor binding to any PDB structure. The virtual chemistry space used for virtual screening is based exclusively on multicomponent reaction chemistry (MCR). Thus any virtual hit can be instantaneously de novo synthesized and the corresponding docking hypothesis can be tested fast. In ANCHOR.QUERY (freely available @ http://anchorquery.csb.pitt.edu/) the concept of anchors, amino acid residues that bury a large amount of solvent accessible surface area at the protein-protein interface is used. Currently ANCHOR.QUERY and the related databases NUCLEO.QUERY and TPP.QUERY harbor a chemical space of &gt;50 million molecules based on &gt;20 different MCR scaffolds. We will discuss the discovery of PPI antagonists for p53/mdm2 and allosteric PDK1 antagonists incl. the design principle and discuss the discovered molecules including synthesis, protein cocrystal structures and biological activities.

Fast generation of novel leads using virtual screening and fast MCR chemistry

253rd National Meeting (2017)

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