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Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

preprint
submitted on 08.10.2019 and posted on 11.10.2019 by Joshua Horton, Alice Allen, Daniel Cole

The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.

Funding

EPSRC EP/R010153/1

History

Email Address of Submitting Author

daniel.cole@ncl.ac.uk

Institution

Newcastle University

Country

United Kingdom

ORCID For Submitting Author

0000-0003-2933-0719

Declaration of Conflict of Interest

no conflict of interest

Licence

Exports