Frags2Drugs: A Novel In Silico Fragment-Based Approach to the Discovery of Kinase Inhibitors

TL;DR

Frags2Drugs is a new computer-based method for designing kinase inhibitors by combining fragments in the ATP-binding site of protein kinases.

Contribution

Frags2Drugs introduces a novel in silico fragment-based drug design approach for generating kinase inhibitors.

Findings

Frags2Drugs successfully reconstructed known co-crystallized ligands and kinase inhibitors.

The method can design various types of inhibitors, including type I, type I1/2, type II, and macrocyclic inhibitors.

Molecular filters improve the selection of kinase inhibitor-like molecules with predicted affinity.

Abstract

Background/Objectives: Fragment-based approaches in the field of drug discovery and design have been widely developed and employed in both academia and industry. We present here an innovative in silico fragment-based drug design approach aimed at designing new inhibitors in the ATP-binding site of protein kinases. Methods: This tool, named Frags2Drugs (F2D), relies on a three-dimensional fragment library obtained from co-crystallized ligands. This library is stored in a graph-oriented database containing the required information to link fragments together. F2D builds every possible molecule that fits into the given cavity on a minute scale. Molecules are then filtered to keep those presenting the best predicted affinity. Several specific molecular filters can be applied, including protein kinase inhibitor-like filters. Results: We validated our method by reconstructing existing co-crystallized ligands and known kinase inhibitors. In this study, we provide several examples of its use to retrieve known or design new type I, type I1/2, type II, and macrocyclic inhibitors on several protein kinases. Conclusions: We have developed an in silico fragment-based ligand design tool able to identify novel kinase inhibitors by growing any scaffolds positioned in the ATP-binding site..

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