Interactive Drug Design with Monte Carlo Simulations

Speaker: Jorge Estrada (BSC)
Date: Wednesday, 2 December 2015, 17:00-18:30
Session: Molecular Dynamics II
Talk type: Extra talk (30 min)

Abstract: Rational drug design highly benefits from an atomic detailed understanding of the protein-ligand interaction mechanism and thermodynamics. Here, in silico modeling offers great possibilities. Such study, however involves dynamic time scales on the range of micro- to milli-seconds, a non-trivial task for current computational software and hardware. Despite these difficulties, and motivated by the pharmaceutical industry, it has centered a great deal of effort from the molecular dynamics (MD) community. Its highest point is probably the recent design and development of the ANTON special purpose machine; development in HPC will certainly impact this field. [1] Using technological advances in protein structure prediction, we have recently introduced PELE (protein energy landscape explorations). PELE combines a Monte Carlo stochastic approach with protein structure prediction algorithms and is capable of accurately reproducing long time scale processes in only few hours of CPU (typically no more than an overnight computing period and, one order of magnitude faster than MD). [2,3] For example, we can map de free (non biased) ligand diffusion and binding, such as the one performed with ANTON at a fraction of the cost, ~16 processors for 24 hours. [4,5] Adding HPC into such sampling capabilities, we are building an interactive – on the flight – modeling tool, capable of combining, in real time, human expertise with in silico predictions. In this talk we will present the methods and our recent developments towards this ambitious aim.

(1) Shan, Y.; Kim, E. T.; Eastwood, M. P.; Dror, R. O.; Seeliger, M. A.; Shaw, D. E. Journal of the American Chemical Society 2011, 133, 9181.
(2) Cossins, B. P.; Hosseini, A.; Guallar, V. Journal of Chemical Theory and Computation 2012.
(3) Borrelli, K. W.; Vitalis, A.; Alcantara, R.; Guallar, V. J. Chem. Theory Comput. 2005, 1, 1304.
(4) Lucas, M. F.; Guallar, V. Biochimica et biophysica acta 2013.
(5) Miki, Y.; Pogni, R.; Acebes, S.; Lucas, F.; Fernández‑Fueyo, E.; Baratto, M. C.; Fernández, M. I.; de los Ríos, V.; Ruiz‑Dueñas, F. J.; Sinicropi, A.; Basosi, R.; Hammel, K. E.; Guallar, V.; Martínez, A. T. Biochemical Journal 2013, 452, 575.