DOI: 10.1002/jcc.20276. Are AM1 ligand‐protein binding enthalpies good enough for use in the rational design of new drugs?

Are AM1 ligand‐protein binding enthalpies good enough for use in the rational design of new drugs?

10.1002/jcc.20276

Crossref journal-article

Wiley

Journal of Computational Chemistry (311)

Abstract

AbstractWe have examined the performance of semiempirical quantum mechanical methods in solving the problem of accurately predicting protein‐ligand binding energies and geometries. Firstly, AM1 and PM3 geometries and binding enthalpies between small molecules that simulate typical ligand‐protein interactions were compared with high level quantum mechanical techniques that include electronic correlation (e.g., MP2 or B3LYP). Species studied include alkanes, aromatic systems, molecules including groups with hypervalent sulfur or with donor or acceptor hydrogen bonding capability, as well as ammonium or carboxylate ions. B3LYP/6‐311+G(2d,p) binding energies correlated very well with the BSSE corrected MP2/6‐31G(d) values. AM1 binding enthalpies also showed good correlation with MP2 values, and their systematic deviation is acceptable when enthalpies are used for the comparison of interaction energies between ligands and a target. PM3 otherwise gave erratic energy differences in comparison to the B3LYP or MP2 approaches. As one would expect, the geometries of the binding complexes showed the known limitations of the semiempirical and DFT methods. AM1 calculations were subsequently applied to a test set consisting of “real” protein active site‐ligand complexes. Preliminary results indicate that AM1 could be a valuable tool for the design of new drugs using proteins as templates. This approach also has a reasonable computational cost. The ligand‐protein X‐ray structures were reasonably reproduced by AM1 calculations and the corresponding AM1 binding enthalpies are in agreement with the results from the “small molecules” test set. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1347–1358, 2005

Bibliography

Villar, R., Gil, M. J., GarcÃa, J. I., & MartÃnezâMerino, V. (2005). Are AM1 ligandâprotein binding enthalpies good enough for use in the rational design of new drugs? Journal of Computational Chemistry, 26(13), 1347â1358. Portico.

Authors 4

R. Villar (first)
M. J. Gil (additional)
J. I. García (additional)
V. Martínez‐Merino (additional)

References 74 Referenced 38

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Dates

Type	When
Created	20 years, 1 month ago (July 14, 2005, 9:15 a.m.)
Deposited	1 year, 11 months ago (Sept. 28, 2023, 2:06 p.m.)
Indexed	4 months, 1 week ago (April 28, 2025, 11:28 a.m.)
Issued	20 years, 1 month ago (July 14, 2005)
Published	20 years, 1 month ago (July 14, 2005)
Published Online	20 years, 1 month ago (July 14, 2005)
Published Print	19 years, 11 months ago (Oct. 1, 2005)

Funders 0

None

BibTeX

@article{Villar_2005, title={Are AM1 ligand‐protein binding enthalpies good enough for use in the rational design of new drugs?}, volume={26}, ISSN={1096-987X}, url={http://dx.doi.org/10.1002/jcc.20276}, DOI={10.1002/jcc.20276}, number={13}, journal={Journal of Computational Chemistry}, publisher={Wiley}, author={Villar, R. and Gil, M. J. and García, J. I. and Martínez‐Merino, V.}, year={2005}, month=jul, pages={1347–1358} }

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