Design of a versatile in silico fragment-based drug design tool – UniversalF2D

Fragment-Based Drug Design (FBDD) is an approach widely developed and used in academic laboratories and pharmaceutical companies for the past twenty years. Nowadays, several drugs approved by the FDA or advanced in clinical trials were discovered from FBDD. To go further and gain in time and efficiency, computational chemistry may be combined with FBDD. We developed in the SB&C team at the ICOA an innovative in silico FBDD tool, Frags2Drugs (F2D), to design new kinase inhibitors directly into the ATP binding site of the desired kinase target. This tool combines a database of hundreds of thousands of experimental 3D fragments, based on graph technologies used by social networks, with an intelligent chemical bond creation approach. Using these approaches, F2D is able to return candidate compounds for a given kinase target from an initial fragment (the seed) chosen by the chemist in few minutes. The tool has been validated on three protein kinases for which were conceived, without any ligand optimisation, selective inhibitors at nanomolar range.
In this project, we aim to go further in this development by extending the application of F2D to all proteins and adding the synthesis feasibility evaluation of proposed compounds by using dedicated IA methodologies and also by integrating the synthesis rules implemented in the DOTS strategy elaborated by the team of Dr Morelli at CRCM in Marseille. To expand the applicability domain of F2D, we plan to exploit the local protein environment of fragments obtained from each protein-ligand complex of the RCSB to enrich our 3D fragment database. This will allow the repositioning of the fragments in the binding site of any protein independently to an alignment of the binding sites. A such 3D fragment database will allow the design of new potent inhibitors by F2D in any protein targets. By using the new FBDD tool developed in this project, called uF2D, we will be able to suggest synthetic feasible compounds to our chemist and biologist partners, selected with the help of physicochemical filters to focus the research on the most promising compounds.
The SB&C team has a well-established knowledge of the protein kinase family and we also rely on the expertise of the team of Dr Morelli on the BRD domain. As first validation step, we will focus on the retrospective design of dual kinase/BRD inhibitors by using uF2D. Indeed, such compounds have already been published on the literature. In the second phase, the methodology will be applied to the design of innovative inhibitors targeting challenging proteins involved in SARS-CoV-2 outbreak, such as nsp10-nsp16 complex, for which Dr. Morelli has a strong expertise.