| Autor: |
Gilabert JF; Barcelona Supercomputing Center , Jordi Girona 29 , E-08034 Barcelona , Spain., Grebner C; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D , AstraZeneca , Gothenburg 431 50 , Sweden., Soler D; Nostrum Biodiscovery , Jordi Girona 29, Nexus II D128 , 08034 Barcelona , Spain., Lecina D; Barcelona Supercomputing Center , Jordi Girona 29 , E-08034 Barcelona , Spain., Municoy M; Barcelona Supercomputing Center , Jordi Girona 29 , E-08034 Barcelona , Spain., Gracia Carmona O; Barcelona Supercomputing Center , Jordi Girona 29 , E-08034 Barcelona , Spain., Soliva R; Nostrum Biodiscovery , Jordi Girona 29, Nexus II D128 , 08034 Barcelona , Spain., Packer MJ; Chemistry, R&D Oncology , AstraZeneca , Cambridge CB4 0QA , United Kingdom., Hughes SJ; Chemistry, R&D Oncology , AstraZeneca , Cambridge CB4 0QA , United Kingdom., Tyrchan C; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D , AstraZeneca , Gothenburg 431 50 , Sweden., Hogner A; Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D , AstraZeneca , Gothenburg 431 50 , Sweden., Guallar V; Barcelona Supercomputing Center , Jordi Girona 29 , E-08034 Barcelona , Spain.; ICREA , Passeig Lluís Companys 23 , E-08010 Barcelona , Spain. |
| Abstrakt: |
In this study, we present a fully automatic platform based on our Monte Carlo algorithm, the Protein Energy Landscape Exploration method (PELE), for the estimation of absolute protein-ligand binding free energies, one of the most significant challenges in computer aided drug design. Based on a ligand pathway approach, an initial short enhanced sampling simulation is performed to identify reasonable starting positions for more extended sampling. This stepwise approach allows for a significant faster convergence of the free energy estimation using the Markov State Model (MSM) technique. PELE-MSM was applied on four diverse protein and ligand systems, successfully ranking compounds for two systems. Based on the results, current limitations and challenges with physics-based methods in computational structural biology are discussed. Overall, PELE-MSM constitutes a promising step toward computing absolute binding free energies and in their application into drug discovery projects. |
