Molecular Lipophilicity in Protein Modeling and Drug Design
Pp. 249-290 (42)
Roman G. Efremov, Anton O. Chugunov, Timothy V. Pyrkov, John P. Priestle, Vladimir M. Pentkovsky, Alexander S. Arseniev and Edgar Jacoby
Hydrophobic interactions play a key role in the folding and maintenance
of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g.,
drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic
(lipophilic) properties of these molecules is indispensable for the development of
efficient computational methods in drug design. One possible solution to the problem
lies in application of a concept of the 3-dimensional molecular hydrophobicity
potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical
parameters evaluated from octanol-water partition coefficients (log P) of numerous
chemical compounds. It permits detailed assessment of the hydrophobic and/or
hydrophilic properties of various parts of molecules and may be useful in analysis of
protein-protein and protein-ligand interactions.
This review surveys recent applications of MHP–based techniques to a number of
biologically relevant tasks. Among them are: (i) Detailed assessment of
hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the
modeling of structure, dynamics, and function of globular and membrane proteins,
membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in
docking simulations for ligands binding to receptors.
It is demonstrated that the application of the MHP-based techniques in combination
with other molecular modeling tools (e.g., Monte Carlo and molecular dynamics
simulations, docking, etc.) permits significant improvement to the standard
computational approaches, provides additional important insights into the intimate
molecular mechanisms driving protein assembling in water and in biological
membranes, and helps in the computer-aided drug discovery process.
Scoring, Docking, Globular proteins, Hydrophobic organization of proteins,
Membrane proteins, Molecular hydrophobicity potential, Protein structure.
M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia