Over the past twenty years, Fragment-Based Drug Design (FBDD) approach has been widely developed and used in academic laboratories and pharmaceutical companies. Today, several drugs approved by the FDA or advanced in clinical trials were discovered from FBDD for example, vemurafenib, a drug targeting the mutated protein kinase BRAF V600E. Here, we present an innovative in silico FBDD tool, Frags2Drugs, which uses fragments to design new kinase inhibitors into the ATP binding site of the target. Positions of the fragments within the cavity were extracted from co-crystalized ligands or obtained by molecular docking. Then, we calculate all the relations (excluded or linked) between these hundreds of thousands of fragments and store them in a graph-oriented database. It allows us to rapidly retrieve all possible connections between fragments for a desired target and using network-based algorithm to build all possible molecules. The first positioned fragment, the seed, is usually proposed by the medicinal chemist as the scaffold of interest. During automatic fragment growing, specific molecular filters are applied to create novel ligands with desired molecular properties or IP. Using kinase inhibitors under development, we also developed an in-house kinase like filters to retrieve most interesting molecules. Finally, each newly identified molecule is docked into the cavity to validate its binding mode. Frags2Drugs was recently applied successfully on several kinase targets such as BRAF and ABL and new kinase inhibitors were identified.

Frags2Drugs: A 3D fragment network to discover new compounds

256th National Meeting (2018)

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