title: Predicting and improving the membrane permeability of peptidic small molecules.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
authors.forename: Salma B
authors.initials: SB
authors.lastname: Rafi
authors.forename: Brian R
authors.initials: BR
authors.lastname: Hearn
authors.forename: Punitha
authors.initials: P
authors.lastname: Vedantham
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001693:Biological Transport, Active; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D002463:Cell Membrane Permeability; D004058:Diffusion; D004285:Dogs; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000596:Amino Acids; D001593:Benzyl Compounds; D002219:Carbamates; D007211:Indoles; D009570:Nitriles; D010455:Peptides; D011725:Pyridines