This work aims to develop in silico methods targeting the key stages of Fragment-Based Drug Design (FBDD), participating to the development of the molecular modeling tool S4MPLE. Briefly, FBDD generates ıdrug-likeı ligands from small organic molecules called fragments. After a validation step of S4MPLE and its energy function, the work focused on FBDD: molecular docking of fragments and their subsequent virtual optimization. The latter mimics standard evolution strategies in FBDD(growing and linking). This in silico approach involves among other two key stages 1) building of a focused library by plugging in pre-generated linkers into reference fragments using rules and 2) sampling of these new compounds under atomic and binding site constraints. Validation simulations, relying on known experimental data, included ıclassicalı growing / linking and more challenging ones (site flexibility, free waters). Finally, this strategy is applied to one project of the company.
Development and validation of molecular modeling tool S4MPLE : application to in silico fragment-based drug design, using molecular docking and virtual optimisation of fragment-like compounds