IBM and NeSC workshop on Protein Science
National e-Science Centre, Edinburgh, March
15-16 2002
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Linear Interaction Energy Approximation for Binding
Affinities of Nevirapine and HEPT Analogues with HIV-1 Reverse Transcriptase Ruhong Zhou 1, Yuk Yin Sham 1, Jed W. Pitera 2, R. A. Friesner 3, Robert Rizzo 4, and W. L. Jorgensen 4 (1) IBM Thomas J Watson Research Center, P O Box 218 & Route 134, Yorktown Heights, NY 10598. (2) IBM Almaden Research Center, D2-402, 650 Harry Road, San Jose, CA 95120 (3) Department of Chemistry, Columbia university, New York, NY 10027 (4) Department of Chemistry, Yale University, New Havens, CT 06520 A fast Linear Interaction Energy method based on a Surface Generalized Born continuum solvent model (LIA-SGB) has been proposed recently for protein-ligand binding affinity predictions. The current study appliesthis method to nevirapine and HEPT analogues binding to HIV-1 reverse transcriptase, examining a data set consisting of a total of 40 ligands. Some discussions about the LIA-SGB fitting schemes and descriptors are presented and comparisons with explicit solvent based LIA methods are made. After including a secondary amide indicator for nevirapine analogues to account for deficiencies in the quantum HF/6-31G* ChelpG derived charges, the LIA-SGB method gives an RMS error of 0.89 kcal/mol (average unsigned error of 0.71 kcal/mol) with a correlation coefficient $r^2$ of 0.74. Leave-one-out cross validation shows a very encouraging RMS error of 1.00 kcal/mol with a correlation coefficient $r^2$ of 0.69. The binding affinities of this binding set are found to be mainly driven by van der Waals interactions and the net loss of ligand cavity energies, while the net electrostatic interactions are found to be anti-binding for this binding set. In addition, for nevirapine analogues, a $\pi$-type hydrogen bond between the NH group of the secondary amide fragments and the phenyl ring of Y188A of HIV-1RT is found to be critical for their otherwise surprising binding affinities. These findings agree very well with previous results from explicit solvent based LIA methods. |
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