Investigating Cryptic Binding Sites by Molecular Dynamics Simulations
Year: 2020
Type: review
Abstract: This Account highlights recent advances and discusses major challenges in investigations of cryptic (hidden) binding sites by molecular simulations. Cryptic binding sites are not visible in protein targets crystallized without a ligand and only become visible crystallographically upon binding events. These sites have been shown to be druggable and might provide a rare opportunity to target difficult proteins. However, due to their hidden nature, they are difficult to find through experimental screening. Computational methods based on atomistic molecular simulations remain one of the best approaches to identify and characterize cryptic binding sites. However, not all methods are equally efficient. Some are more apt at quickly probing protein dynamics but do not provide thermodynamic or druggability information, while others that are able to provide such data are demanding in terms of time and resources. Here, we review the recent contributions of mixed-solvent simulations, metadynamics, Markov state models, and other enhanced sampling methods to the field of cryptic site identification and characterization. We discuss how these methods were able to provide precious information on the nature of the site opening mechanisms, to predict previously unknown sites which were used to design new ligands, and to compute the free energy landscapes and kinetics associated with the opening of the sites and the binding of the ligands. We highlight the potential and the importance of such predictions in drug discovery, especially for difficult ("undruggable") targets. We also discuss the major challenges in the field and their possible solutions.
Source: Accounts of Chemical Research
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: David and Lucile Packard Foundation, Burroughs Wellcome Fund, National Institutes of Health, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, National Institute of General Medical Sciences, Division of Molecular and Cellular Biosciences, H2020 Future and Emerging Technologies
Awards: Allosteric impact of non-active-site mutations on enzymatic function, G2453313107, CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface, Efficient modelling and validation of cryptic protein binding sites for drug discovery, G6610467635, EPSRC Flagship Software - BioSimSpace: A shared space for the community development of biomolecular simulation workflows, Efficient modelling and validation of cryptic protein binding sites for drug discovery, G8891310061
OpenAlex ID: W3009690250