Calculation of Cyclodextrin Binding Affinities: Energy, Entropy, and Implications for Drug Design

¹ Center for Advanced Research in Biotechnology, U. Maryland Biotechnology Institute
² Center for Advanced Research in Biotechnology, U. of Maryland Biotechnology Institut

^* To whom correspondence should be addressed. E-mail: gilson{at}umbi.umd.edu.

Submitted on July 13, 2004
Revised on August 5, 2004
Accepted on 18 August 2004

	Abstract

The second generation Mining Minima method yields binding affinities accurate to within 0.8 kcal/mol for the associations of -, - and -cyclodextrin with benzene, resorcinol, flurbiprofen, naproxen and nabumetone. These calculations require hours to a day on a commodity computer. The calculations also indicate that the changes in configurational entropy upon binding oppose binding by as much as 24 kcal/mol and result primarily from a narrowing of energy wells in the bound versus the free state, rather than from a drop in the number of distinct low-energy conformations on binding. Also, the configurational entropy is found to vary substantially among the bound conformations of a given cyclodextrin-guest complex. This result suggests that the configurational entropy must be accounted for in order to reliably ranking docked conformations in both host-guest and ligand-protein complexes. In close analogy with the common experimental observation of entropy-enthalpy compensation, the computed entropy changes show a near-linear relationship with the change in mean potential plus solvation energy.

Key Words: NSAID, compensation, free energy, host-guest, mining minima, predominant states

This article has been cited by other articles:

				M. V. Rekharsky, T. Mori, C. Yang, Y. H. Ko, N. Selvapalam, H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L. Isaacs, et al. A synthetic host-guest system achieves avidin-biotin affinity by overcoming enthalpy entropy compensation PNAS, December 26, 2007; 104(52): 20737 - 20742. [Abstract] [Full Text] [PDF]

				M. S. Lee and M. A. Olson Calculation of Absolute Protein-Ligand Binding Affinity Using Path and Endpoint Approaches Biophys. J., February 1, 2006; 90(3): 864 - 877. [Abstract] [Full Text] [PDF]