Understanding ligand-receptor recognition by means of high-throughput molecular dynamics : a perspective for drug discovery

Ferruz Capapey, Noelia

Understanding ligand-receptor recognition by means of high-throughput molecular dynamics : a perspective for drug discovery

Document Type

Doctoral thesis
Published Version

Author

Ferruz Capapey, Noelia

Director

De Fabritiis, Gianni
Sanz, Ferran

Publication Date

2016-03-04

Pages

174 p.

Citation

Ferruz Capapey, N. Understanding ligand-receptor recognition by means of high-throughput molecular dynamics : a perspective for drug discovery. Universitat Pompeu Fabra; 2016. handle: http://hdl.handle.net/10803/363212

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

Understanding how receptor-ligand interactions occur is a first step towards designing new drugs. The complete reconstruction of the binding process in a drug-receptor system provides all the physical-chemistry variables for rational design of inhibitors of a chosen target, an important step in drug discovery. Although very powerful, direct experimental observation of full binding processes is very hard to perform. In this thesis, by using high-throughput molecular dynamics in the distributed computing project GPUGRID.net and analysing the resulting data by Markov state models (MSM), we successfully estimated kinetics, thermodynamics and binding modes for different molecular systems. In the initial works, we focused on estimating the potency of inhibitor-protein complexes. In subsequent studies, we described more complex pictures of binding, taking into account the receptor dynamics or other binding molecules. The results are promising and establish the methodology as a very powerful tool in the first stages of the drug discovery pipeline.
Comprender las interacciones entre proteína y ligando es el primer paso para diseñar nuevos medicamentos. Llegar a reconstruir completamente este proceso de unión proporciona todas las variables físico-químicas para una optimización racional, un paso muy importante en el descubrimiento de fármacos. Pese a que esto ofrece muchas ventajas, todavía es complicado observar estos procesos experimentalmente. En esta tesis, utilizando simulaciones moleculares de alto rendimiento (HTMD) mediante el proyecto distribuido GPUGRID.net y análisis por Markov state models (MSM), hemos obtenido datos cinéticos, termodinámicos y modos de unión para varios sistemas. En los primeros trabajos nos centramos en estimar la afinidad entre complejos inhibidor-proteína. En trabajos posteriores, logramos caracterizar completamente rutas de unión del ligando teniendo en cuenta los confórmeros de la proteína u otros ligandos presentes. Los resultados son prometedores y establecen la utilidad de HTMD en las primeras fases de descubrimiento de fármacos

Keywords

Molecular dynamics, High-throughput, Drug discovery, Ligand binding, Markov state models, Dinàmica molecular, Medicaments-Descobriment, Lligands (Bioquímica)