Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water.

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Cozzini P, Fornabaio M, Marabotti A, Abraham DJ, Kellogg GE, Mozzarelli A

Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 1. Models without explicit constrained water.

J Med Chem. 2002 Jun 6;45(12):2469-83.

PubMed ID

12036355 [ View in PubMed

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Abstract

The prediction of the binding affinity between a protein and ligands is one of the most challenging issues for computational biochemistry and drug discovery. While the enthalpic contribution to binding is routinely available with molecular mechanics methods, the entropic contribution is more difficult to estimate. We describe and apply a relatively simple and intuitive calculation procedure for estimating the free energy of binding for 53 protein-ligand complexes formed by 17 proteins of known three-dimensional structure and characterized by different active site polarity. HINT, a software model based on experimental LogP(o/w) values for small organic molecules, was used to evaluate and score all atom-atom hydropathic interactions between the protein and the ligands. These total scores (H(TOTAL)), which have been previously shown to correlate with DeltaG(interaction) for protein-protein interactions, correlate with DeltaG(binding) for protein-ligand complexes in the present study with a standard error of +/-2.6 kcal mol(-1) from the equation DeltaG(binding) = -0.001 95 H(TOTAL) - 5.543. A more sophisticated model, utilizing categorized (by interaction class) HINT scores, produces a superior standard error of +/-1.8 kcal mol(-1). It is shown that within families of ligands for the same protein binding site, better models can be obtained with standard errors approaching +/-1.0 kcal mol(-1). Standardized methods for preparing crystallographic models for hydropathic analysis are also described. Particular attention is paid to the relationship between the ionization state of the ligands and the pH conditions under which the binding measurements are made. Sources and potential remedies of experimental and modeling errors affecting prediction of DeltaG(binding) are discussed.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-Phenylbutylamine	Trypsin-1	Ki (nM)	20000	N/A	N/A	Details
Oleic Acid	Fatty acid-binding protein, adipocyte	Kd (nM)	58000	N/A	N/A	Details
Palmitic Acid	Fatty acid-binding protein, adipocyte	Kd (nM)	83000	N/A	N/A	Details