Drug permeability prediction using PMF method

Drug permeability determines the oral availability of drugs via cellular membranes. Poor permeability makes a drug unsuitable for further development. The permeability may be estimated as the free energy change that the drug should overcome through crossing membrane. In this paper the drug permeability was simulated using molecular dynamics method and the potential energy profile was calculated with potential of mean force (PMF) method. The membrane was simulated using DPPC bilayer and three drugs with different permeability were tested. PMF studies on these three drugs show that doxorubicin (low permeability) should pass higher free energy barrier from water to DPPC bilayer center while ibuprofen (high permeability) has a lower energy barrier. Our calculation indicates that the simulation model we built is suitable to predict drug permeability.

[1]  H. Berendsen,et al.  Molecular dynamics simulations of a fully hydrated dipalmitoylphosphatidylcholine bilayer with different macroscopic boundary conditions and parameters , 1996 .

[2]  Ramanan Krishnamoorti,et al.  Partitioning of nonsteroidal antiinflammatory drugs in lipid membranes: a molecular dynamics simulation study. , 2010, Biophysical journal.

[3]  Bert L. de Groot,et al.  g_wham—A Free Weighted Histogram Analysis Implementation Including Robust Error and Autocorrelation Estimates , 2010 .

[4]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[5]  T. Xiang,et al.  The Barrier Domain for Solute Permeation Varies With Lipid Bilayer Phase Structure , 1998, The Journal of Membrane Biology.

[6]  Parminder Singh,et al.  In Silico Prediction of Drug Permeability Across Buccal Mucosa , 2009, Pharmaceutical Research.

[7]  Jonathan W Essex,et al.  Permeability of small molecules through a lipid bilayer: a multiscale simulation study. , 2009, The journal of physical chemistry. B.

[8]  R. Larson,et al.  Molecular dynamics simulations of model trans-membrane peptides in lipid bilayers: a systematic investigation of hydrophobic mismatch. , 2006, Biophysical journal.

[9]  Matthew P Jacobson,et al.  Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. , 2006, Journal of the American Chemical Society.

[10]  Ulf Norinder,et al.  Theoretical Calculation and Prediction of Caco-2 Cell Permeability Using MolSurf Parametrization and PLS Statistics , 1997, Pharmaceutical Research.

[11]  Jonathan W. Essex,et al.  Permeability of drugs and hormones through a lipid bilayer: insights from dual-resolution molecular dynamics† , 2010 .

[12]  W F Drew Bennett,et al.  Distribution of amino acids in a lipid bilayer from computer simulations. , 2008, Biophysical journal.

[13]  Paulo Paixão,et al.  Prediction of the in vitro permeability determined in Caco-2 cells by using artificial neural networks. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[14]  A. W. Schüttelkopf,et al.  PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. , 2004, Acta crystallographica. Section D, Biological crystallography.

[15]  Alexander D. MacKerell,et al.  Computational model for predicting chemical substituent effects on passive drug permeability across parallel artificial membranes. , 2008, Molecular pharmaceutics.

[16]  Robert V. Swift,et al.  Modeling the pharmacodynamics of passive membrane permeability , 2011, J. Comput. Aided Mol. Des..

[17]  O. Berger,et al.  Molecular dynamics simulations of a fluid bilayer of dipalmitoylphosphatidylcholine at full hydration, constant pressure, and constant temperature. , 1997, Biophysical journal.

[18]  Alexander Kyrychenko,et al.  Partitioning of 2,6-Bis(1H-Benzimidazol-2-yl)pyridine fluorophore into a phospholipid bilayer: complementary use of fluorescence quenching studies and molecular dynamics simulations. , 2011, Biophysical chemistry.

[19]  Karel Berka,et al.  Convergence of Free Energy Profile of Coumarin in Lipid Bilayer , 2012, Journal of chemical theory and computation.

[20]  Wei Zhang,et al.  Recent advances in computational prediction of drug absorption and permeability in drug discovery. , 2006, Current medicinal chemistry.

[21]  Kui Wang,et al.  Studies of intestinal permeability of 36 flavonoids using Caco-2 cell monolayer model. , 2009, International journal of pharmaceutics.

[22]  P. Sinko,et al.  Estimating Human Drug Oral Absorption Kinetics from Caco-2 Permeability Using an Absorption-Disposition Model: Model Development and Evaluation and Derivation of Analytical Solutions for ka and Fa , 2005, Journal of Pharmacology and Experimental Therapeutics.