Abstract:
:In drug discovery, it is essential to identify binding sites on protein surfaces that drug-like molecules could exploit to exert a biological effect. Both X-ray crystallography and NMR experiments have demonstrated that organic solvents bind precisely at these locations. We show that this effect is reproduced using molecular dynamics with a binary solvent. Furthermore, analysis of the simulations give direct access to interaction free energies between the protein and small organic molecules, which can be used to detect binding sites and to predict the maximal affinity that a drug-like molecule could attain for them. On a set of pharmacologically relevant proteins, we obtain good predictions for druggable sites as well as for protein-protein and low affinity binding sites. This is the first druggability index not based on surface descriptors and, being independent of a training set, is particularly indicated to study unconventional targets such as protein-protein interactions or allosteric binding sites.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Seco J,Luque FJ,Barril Xdoi
10.1021/jm801385dsubject
Has Abstractpub_date
2009-04-23 00:00:00pages
2363-71issue
8eissn
0022-2623issn
1520-4804journal_volume
52pub_type
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