Commun. Comput. Phys., 13 (2013), pp. 31-60.


Computational Modeling of Solvent Effects on Protein-Ligand Interactions Using Fully Polarizable Continuum Model and Rational Drug Design

Fang Zheng 1, Chang-Guo Zhan 1*

1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky 40536, USA.

Received 13 September 2011; Accepted (in revised version) 12 October 2011
Available online 12 June 2012
doi:10.4208/cicp.130911.121011s

Abstract

This is a brief review of the computational modeling of protein-ligand interactions using a recently developed fully polarizable continuum model (FPCM) and rational drug design. Computational modeling has become a powerful tool in understanding detailed protein-ligand interactions at molecular level and in rational drug design. To study the binding of a protein with multiple molecular species of a ligand, one must accurately determine both the relative free energies of all of the molecular species in solution and the corresponding microscopic binding free energies for all of the molecular species binding with the protein. In this paper, we aim to provide a brief overview of the recent development in computational modeling of the solvent effects on the detailed protein-ligand interactions involving multiple molecular species of a ligand related to rational drug design. In particular, we first briefly discuss the main challenges in computational modeling of the detailed protein-ligand interactions involving the multiple molecular species and then focus on the FPCM model and its applications. The FPCM method allows accurate determination of the solvent effects in the first-principles quantum mechanism (QM) calculations on molecules in solution. The combined use of the FPCM-based QM calculations and other computational modeling and simulations enables us to accurately account for a protein binding with multiple molecular species of a ligand in solution. Based on the computational modeling of the detailed protein-ligand interactions, possible new drugs may be designed rationally as either small-molecule ligands of the protein or engineered proteins that bind/metabolize the ligand. The computational drug design has successfully led to discovery and development of promising drugs.


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PACS: 31, 82, 87
Key words: Protein-ligand interaction, solvent effect, rational drug design, binding affinity.

*Corresponding author.
Email: fzhen2@email.uky.edu (F. Zheng), zhan@uky.edu (C.-G. Zhan)
 

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