Predicting and Improving the Membrane Permeability of Peptidic Small Molecules

Citations Over TimeTop 10% of 2012 papers

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.

Related Papers

• → A molecular mechanics force field for lignin(2008)98 cited
• → A molecular mechanics force field for conformational analysis of aliphatic acyclic amines(1990)18 cited
• → Amino-acid-dependent main-chain torsion-energy terms for protein systems(2013)6 cited
• → Shallow acceptor level in GaAs crystals resulting from Cu diffusion(1964)15 cited
• → A Proposal for Amino Acid Dependent Main-Chain Torsion-Energy Terms for Protein Force Fields(2013)