PhD Project ESR2


Molecular Modeling and Virtual Screening for Rational Design of Tubulin-Protein Interaction Modulators

Supervisors

Prof. Alexandre Varnek, University of Strasbourg
Dr.Dragos Horvath, University of Strasbourg
Prof. Marta Cascante, University of Barcelona (secondment)

Involved Universities

University of Strasbourg
University of Barcelona

Involved Company

AnkarPharma, Madrid, Spain

PhD COURSES

Ecole Doctorale des Sciences Chimiques (UNISTRA) Biotechnology (UB)

Objectives

Design of novel, and adaptation of existing in-house modeling and virtual screening tools to the context of PPI (Protein-Protein interaction) modulator discovery, and their application to generate/prioritize new molecules for synthesis/purchase and test.

DESCRIPTION OF THE PROJECT

This multivalent PhD project is aimed at in Silico prioritization/focused library design of peptide based molecular probes able to modulate the Tubulin Tau and α-Synuclein protein network. To this purpose, the protein-protein interaction interfaces will be analysed, in order to detect putative binding sites/binding pharmacophores for the putative ligands. In parallel, examples of any existing modulators will be mined from literature and public databases, in order to serve for ligand-based virtual screening strategies. The library of relevant polypeptides will be enumerated in Silico and prioritized by the above-developed virtual screening strategies. This can be extended to libraries of organic molecules, should an alternative to peptide modulators be proven of interest. Validity of candidates will be evaluated by docking. To this latter purpose, methodological developments of our in-house program S4MPLE. This tool was designed such as to allow the simulation of virtually any inter and intramolecular interaction scenarios. However, more development is currently needed, notably (1) the steady improvement of force field parameterization, by switching to a more realistic Generalized Born solvent model and (2) enabling S4MPLE to model protein-protein. Therefore, the candidate is expected to already possess a master-level knowledge of chemoinformatics, be already acquainted with basic molecular structure handling, the concepts of similarity search, molecular structure encoding as descriptors, QSAR and pharmacophore models and the principles of docking (force field theory, solvent models) and programming skills. The ESR will be enrolled by the University of Strasbourg (https://www.unistra.it/) under the supervision of Prof. Alexandre Varnek and Dr. Dragos Horvath. The ESR will be awarded a Double Doctorate degree in co-tutelle with the University of Barcelona, under the supervision of Prof. Marta Cascante. The research will involve secondments to the University of Barcelona and to the company AnkarPharma in Madrid, Spain. The selected candidate will participate in the network’s training activities and work placements in the laboratories of the participating academic and industrial partners.