ISSN:
0020-7608
Keywords:
molecular dynamics
;
binding free energy
;
structure-based ligand design
;
linear response
;
Chemistry
;
Theoretical, Physical and Computational Chemistry
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
A recently developed method for predicting binding affinities in ligand-receptor complexes, based on interaction energy averaging and conformational sampling by molecular dynamics simulation, is presented. Polar and nonpolar contributions to the binding free energy are approximated by a linear scaling of the corresponding terms in the average intermolecular interaction energy for the bound and free states of the ligand. While the method originally assumed the validity of electrostatic linear response, we show that incorporation of systematic deviations from linear response derived from free energy perturbation calculations enhances the accuracy of the approach. The method is applied to complexes of wild-type and mutant human dihydrofolate reductases with 2,4-diaminopteridine and 2,4-diaminoquinazoline inhibitors. It is shown that a binding energy accuracy of about 1 kcal/mol is attainable even for multiply ionized compounds, such as methotrexate, for which electrostatic interactions energies are very large. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 69: 77-88, 1998
Additional Material:
5 Ill.
Type of Medium:
Electronic Resource
Permalink
