Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field

• Type: Article in International Scientific Journal
• Date: 2014

Authors

Silvia A Martins (Author) Other; Sergio F Sousa (Author) Other; Maria Joao Ramos (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Journal of Chemical Theory and Computation

Vol. 10

Pages: 3570-3577

ISSN: 1549-9618

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 29 Citations

Scopus - 29 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-009-RV1

DOI: 10.1021/ct500346y

Abstract (EN): Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The determination of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (Delta Delta G(solv)) for a total of 92 transformations in small molecules was predicted using Thermodynamic Integration (TI). It was our aim to compare experimental and calculated solvation free energies for typical and prime additions considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between experimental and predicted values, with an overestimation of the predicted values for CH3, halogens, and NH2, as well as an underestimation for CONH2, but all fall within +/-1 kcal/mol. NO2 addition showed a larger and systematic underestimation of the predicted Delta Delta G(solv), indicating the need for special attention in these cases. For small molecules, if no experimental data is available, using TI as a theoretical strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8