Contribution of Conformer Focusing to the Uncertainty in Predicting Free Energies for Protein−Ligand Binding
- 12 September 2006
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (20) , 5880-5884
- https://doi.org/10.1021/jm060763i
Abstract
When a ligand binds to a protein, it is typically not in the lowest-energy conformation for the unbound ligand and there is also a loss of conformational degrees of freedom. The free-energy change for this "conformer focusing" is addressed here formally, and the associated errors with its estimation or neglect are considered in the context of scoring functions for protein-ligand docking and computation of absolute free energies of binding. Specific applications for inhibition of HIV-1 reverse transcriptase are reported. It is concluded that the uncertainties from this source alone are sufficient to preclude the viability of current docking methodology for rank-ordering of diverse compounds in high-throughput virtual screening.Keywords
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