Obiettivo "Although protein dynamics plays an essential role in function, it is rarely considered explicitly in current structure-based approaches to drug design. Here I propose the computer-aided design of ligands by modulation of protein dynamics, or equivalently, protein structural ensembles. The detailed understanding of ligand-induced perturbations of protein dynamics that will result from this study is crucial not just to accurately predicting binding affinities and tackling ""undruggable"" targets, but also to understanding protein allostery.Three major aims will be pursued during this project.First, I will combine concepts from chemoinformatics and non-equilibrium thermodynamics to detect cryptic ""druggable"" small molecule binding sites in computed structural ensembles. New computational methods will be developed to predict how binding at these putative sites is likely to influence protein function. This will enable rational approaches to allosteric control of protein function.Second, new classes of non-equilibrium sampling algorithms will be developed to improve by 2-3 orders of magnitude the speed of computation of protein/ligand structural ensembles by molecular simulations. This will enable routine consideration of protein flexibility in ligand optimisation problems.Third, I will address with the above methods a frontier problem in molecular recognition: the rational design of protein isoform-specific ligands. To achieve this goal, I will integrate computation with experiments and focus efforts on the therapeutically relevant cyclophilin protein family. Experimental work will involve the use of purchased or custom-synthesized competitive and allosteric ligands in enzymatic assays, calorimetry and crystal structure analyses.Overall, this project proposes fundamental advances in our ability to quantify and engineer protein-ligand interactions, therefore expanding opportunities for the development of future small molecule therapeutics." Campo scientifico medical and health sciencesbasic medicinemedicinal chemistrynatural sciencesphysical sciencesthermodynamicsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencescomputer and information sciencescomputational sciencenatural scienceschemical sciencesanalytical chemistrycalorimetry Programma(i) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) ERC-SG-PE4 - ERC Starting Grant - Physical and Analytical Chemical sciences Invito a presentare proposte ERC-2013-StG Vedi altri progetti per questo bando Meccanismo di finanziamento ERC-SG - ERC Starting Grant Istituzione ospitante THE UNIVERSITY OF EDINBURGH Contributo UE € 1 382 202,00 Indirizzo OLD COLLEGE, SOUTH BRIDGE EH8 9YL Edinburgh Regno Unito Mostra sulla mappa Regione Scotland Eastern Scotland Edinburgh Tipo di attività Higher or Secondary Education Establishments Ricercatore principale Julien Michel (Dr.) Contatto amministrativo Alan Kennedy (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato Beneficiari (1) Classifica in ordine alfabetico Classifica per Contributo UE Espandi tutto Riduci tutto THE UNIVERSITY OF EDINBURGH Regno Unito Contributo UE € 1 382 202,00 Indirizzo OLD COLLEGE, SOUTH BRIDGE EH8 9YL Edinburgh Mostra sulla mappa Regione Scotland Eastern Scotland Edinburgh Tipo di attività Higher or Secondary Education Establishments Ricercatore principale Julien Michel (Dr.) Contatto amministrativo Alan Kennedy (Mr.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato