Structural and conformational determinants of macrocycle cell permeability.

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

[1]  M. Waring.  Lipophilicity in drug discovery , 2010, Expert Opinion on Drug Discovery.

[2]  Chad E. Townsend,et al.  Going Out on a Limb: Delineating The Effects of β-Branching, N-Methylation, and Side Chain Size on the Passive Permeability, Solubility, and Flexibility of Sanguinamide A Analogues. , 2015, Journal of medicinal chemistry.

[3]  Siegfried S. F. Leung,et al.  Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. , 2015, Journal of the American Chemical Society.

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

[5]  G. M. Pollack,et al.  Kinetic Considerations for the Quantitative Assessment of Efflux Activity and Inhibition: Implications for Understanding and Predicting the Effects of Efflux Inhibition , 2007, Pharmaceutical Research.

[6]  K. Luthman,et al.  Caco-2 monolayers in experimental and theoretical predictions of drug transport. , 2001, Advanced drug delivery reviews.

[7]  Stephen P. Hale,et al.  The exploration of macrocycles for drug discovery — an underexploited structural class , 2008, Nature Reviews Drug Discovery.

[8]  Eamon Comer,et al.  Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles , 2011, Proceedings of the National Academy of Sciences.

[9]  HO NOOOMeOMeMeMeOOHMeOMeMeOOOHMeOOOHOHMeMe,et al.  Macrocycles in new drug discovery , 2008 .

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

[11]  Per Artursson,et al.  Rapid measurement of intracellular unbound drug concentrations. , 2013, Molecular pharmaceutics.

[12]  P. Artursson,et al.  Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers , 2007, Nature Protocols.

[13]  Wolfgang Bermel,et al.  Gradient selection in inverse heteronuclear correlation spectroscopy , 1993 .

[14]  C. Heinis,et al.  Drug discovery: tools and rules for macrocycles. , 2014, Nature chemical biology.

[15]  C. Moonen,et al.  Rapid recording of solvent-suppressed 2D COSY spectra with inherent quadrature detection using pulsed field gradients , 1991 .

[16]  Fabrizio Giordanetto,et al.  Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? , 2014, Journal of medicinal chemistry.

[17]  Dima Kozakov,et al.  How Proteins Bind Macrocycles , 2014, Nature chemical biology.

[18]  Wolfgang H. B. Sauer,et al.  Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity , 2003, J. Chem. Inf. Comput. Sci..

[19]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[20]  Spiros Liras,et al.  Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability. , 2015, European journal of medicinal chemistry.

[21]  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.

[22]  Stuart L. Schreiber,et al.  Organic chemistry: Molecular diversity by design , 2009, Nature.

[23]  G. V. Paolini,et al.  Quantifying the chemical beauty of drugs. , 2012, Nature chemistry.

[24]  Ulf Norinder,et al.  Identification of Novel Specific and General Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp, BCRP and MRP2 Among Registered Drugs , 2009, Pharmaceutical Research.

[25]  Ulf Norinder,et al.  Exploring the role of different drug transport routes in permeability screening. , 2005, Journal of medicinal chemistry.

[26]  D. Marion.  Rotating frame nuclear overhauser effect: a practical tool for the 1H NMR study of peptides in solution , 1985 .

[27]  Matthew P Jacobson,et al.  Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products. , 2015, Journal of medicinal chemistry.

[28]  Thomas J. Raub,et al.  P-glycoprotein recognition of substrates and circumvention through rational drug design. , 2006, Molecular pharmaceutics.

[29]  S. Hitchcock,et al.  Structural modifications that alter the P-glycoprotein efflux properties of compounds. , 2012, Journal of medicinal chemistry.

[30]  David J. Craik,et al.  Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients , 2014, Proceedings of the National Academy of Sciences.

[31]  Chih-Jen Lin,et al.  LIBSVM: A library for support vector machines , 2011, TIST.

[32]  Thomas J. Raub,et al.  How hydrogen bonds impact P-glycoprotein transport and permeability. , 2012, Bioorganic & medicinal chemistry letters.

[33]  Ricardo J. Ferreira,et al.  Molecular Docking Characterizes Substrate-Binding Sites and Efflux Modulation Mechanisms within P-Glycoprotein , 2013, J. Chem. Inf. Model..

[34]  Cristiano Ruch Werneck Guimarães,et al.  Use of 3D Properties to Characterize Beyond Rule-of-5 Property Space for Passive Permeation , 2012, J. Chem. Inf. Model..

[35]  A. Leo,et al.  An NMR method for the quantitative assessment of intramolecular hydrogen bonding; application to physicochemical, environmental, and biochemical properties. , 2014, The Journal of organic chemistry.

[36]  T. Blundell,et al.  Structural biology and drug discovery of difficult targets: the limits of ligandability. , 2012, Chemistry & biology.

[37]  Fabrizio Giordanetto,et al.  Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. , 2014, Chemistry & biology.

[38]  Robert M. Harris,et al.  Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties. , 2015, Bioorganic & medicinal chemistry.

[39]  F. Lovering,et al.  Escape from Flatland 2: complexity and promiscuity , 2013 .

[40]  Carol A. Mulrooney,et al.  Build/couple/pair strategy for the synthesis of stereochemically diverse macrolactams via head-to-tail cyclization. , 2012, ACS combinatorial science.

[41]  Kim L R Brouwer,et al.  The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice , 2006, Molecular Pharmacology.

[42]  Nathan T. Ross,et al.  An aldol-based build/couple/pair strategy for the synthesis of medium- and large-sized rings: discovery of macrocyclic histone deacetylase inhibitors. , 2010, Journal of the American Chemical Society.

[43]  Leo Breiman,et al.  Random Forests , 2001, Machine Learning.

[44]  P. Artursson,et al.  Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. , 1991, Biochemical and biophysical research communications.

[45]  Bradley C Doak,et al.  How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets. , 2016, Journal of medicinal chemistry.

[46]  Peteris Prusis,et al.  Unbiased descriptor and parameter selection confirms the potential of proteochemometric modelling , 2005, BMC Bioinformatics.

[47]  R Scott Obach,et al.  Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination. , 2010, Journal of medicinal chemistry.

[48]  Spiros Liras,et al.  Improving on nature: making a cyclic heptapeptide orally bioavailable. , 2014, Angewandte Chemie.

[49]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[50]  Yun Alelyunas,et al.  Application of a Dried-DMSO rapid throughput 24-h equilibrium solubility in advancing discovery candidates. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[51]  B. Samuelsson,et al.  Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor. , 2014, Journal of medicinal chemistry.