Predicting and improving the membrane permeability of peptidic small molecules.

We evaluate experimentally and computationally the membrane permeability of matched sets of peptidic small molecules bearing natural or bioisosteric unnatural amino acids. We find that the intentional introduction of hydrogen bond acceptor-donor pairs in such molecules can improve membrane permeability while retaining or improving other favorable drug-like properties. We employ an all-atom force field based method to calculate changes in free energy associated with the transfer of the peptidic molecules from water to membrane. This computational method correctly predicts rank order experimental permeability trends within congeneric series and is much more predictive than calculations (e.g., clogP) that do not consider three-dimensional conformation.

[1]  J J Baldwin,et al.  Prediction of drug absorption using multivariate statistics. , 2000, Journal of medicinal chemistry.

[2]  Alexander Alex,et al.  Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space , 2011 .

[3]  Sven Frokjaer,et al.  Predicting Drug Absorption from Molecular Surface Properties Based on Molecular Dynamics Simulations , 1998, Pharmaceutical Research.

[4]  R. Friesner,et al.  Generalized Born Model Based on a Surface Integral Formulation , 1998 .

[5]  M. Hashida,et al.  Prediction of Caco-2 cell permeability using a combination of MO-calculation and neural network. , 2002, International journal of pharmaceutics.

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

[7]  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.

[8]  Matthew P. Jacobson,et al.  Predicting Binding to P-Glycoprotein by Flexible Receptor Docking , 2011, PLoS Comput. Biol..

[9]  J. Vederas,et al.  Reaction of trimethylsilylamines with N-Cbz-L-serine-β-lactone: A convenient route to optically pure β-amino-L-alanine derivatives , 1994 .

[10]  Markus A. Lill,et al.  A Medicinal Chemist's Guide to Molecular Interactions , 2013 .

[11]  B. Kuhn,et al.  Intramolecular hydrogen bonding in medicinal chemistry. , 2010, Journal of medicinal chemistry.

[12]  Kazuya Nakao,et al.  Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes: application to prediction of Caco-2 cell permeability. , 2005, Bioorganic & medicinal chemistry.

[13]  S. McCleary,et al.  Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist. , 2001, Journal of medicinal chemistry.

[14]  Terry R. Stouch,et al.  Orientation and Diffusion of a Drug Analog in Biomembranes: Molecular Dynamics Simulations , 1995 .

[15]  Herman J. C. Berendsen,et al.  Permeation Process of Small Molecules across Lipid Membranes Studied by Molecular Dynamics Simulations , 1996 .

[16]  J. Essex,et al.  Behaviour of small solutes and large drugs in a lipid bilayer from computer simulations. , 2005, Biochimica et biophysica acta.

[17]  Matthew P. Jacobson,et al.  An atomistic model of passive membrane permeability: application to a series of FDA approved drugs , 2007, J. Comput. Aided Mol. Des..

[18]  Jonathan W. Essex,et al.  Permeation of small molecules through a lipid bilayer: a computer simulation study , 2004 .

[19]  J. Essex,et al.  Computer simulation of small molecule permeation across a lipid bilayer: dependence on bilayer properties and solute volume, size, and cross-sectional area. , 2004, Biophysical journal.

[20]  Jeremy R. Greenwood,et al.  Epik: a software program for pKa prediction and protonation state generation for drug-like molecules , 2007, J. Comput. Aided Mol. Des..

[21]  S. Ekins,et al.  Progress in predicting human ADME parameters in silico. , 2000, Journal of pharmacological and toxicological methods.

[22]  M. Gilson,et al.  Nucleic acid base-pairing and N-methylacetamide self-association in chloroform: affinity and conformation. , 1999, Biophysical chemistry.

[23]  R. Friesner,et al.  Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides† , 2001 .

[24]  Sean Ekins,et al.  Three-Dimensional Quantitative Structure-Permeability Relationship Analysis for a Series of Inhibitors of Rhinovirus Replication , 2001, J. Chem. Inf. Comput. Sci..

[25]  Yizhong Zhang,et al.  On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds , 2011, Nature chemical biology.

[26]  Berith F. Jensen,et al.  In silico prediction of membrane permeability from calculated molecular parameters. , 2005, Journal of medicinal chemistry.

[27]  W. L. Jorgensen,et al.  The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. , 1988, Journal of the American Chemical Society.

[28]  Matthew P Jacobson,et al.  Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. , 2006, Journal of the American Chemical Society.