Premium
Protein–drug interactions: Characterization of inhibitor binding in complexes of DHFR with trimethoprim and related derivatives
Author(s) -
Fleischmann Stephen H.,
Brooks Charles L.
Publication year - 1990
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.340070106
Subject(s) - molecular dynamics , trimethoprim , chemistry , drug , binding energy , computational chemistry , thermodynamics , simple (philosophy) , biochemistry , physics , biology , pharmacology , nuclear physics , antibiotics , philosophy , epistemology
Structural and thermodynamic interactions for the binding of trimethoprim and related congeners to the binary complex of diphydrofolate reductase (from chicken) and NADPH are explored using free energy simulation methods. Good agreement between structures from experimental X‐ray refinement and molecular dynamics simulations is found for the complexes. Agreement with thermodyanmic measurements is found as well. Our thermodynamic calculations suggest that entropic contributions and desolvation thermodynamics can play a crucial role in overall bindings, and that extreme care must be taken in the use of simple model building to rationalize or predict protein–drug binding.