Decades of drug-discovery research have shown that drug molecules that need to cross the cell membrane exhibit a relatively narrow range of physicochemical properties, e.g., molecular mass, hydrophobicity and polarity. A recent survey of a dataset of human approved drugs has found that 27% of these are aliphatic amines and 20% are carboxylic acids [1,2]. In an aqueous environment at neutral pH, aliphatic amines have a propensity to be protonated and carry an electric charge of +1e. Similarly, carboxylic acids tend to be deprotonated and carry an electric charge of −1e. 

Given the low permeability of the cell membrane to charged species, the mechanism allowing aliphatic amine and carboxylic aciddrugs to permeate through the lipid phase of the membrane becomes of interest. (Perhaps surprisingly, neutral drugs were determined to constitute only 20% of all human approved drugs [1].) We hypothesize that, whatever the specificity these groups may provide during the biological action of the drug, aliphatic amine and carboxylic acid moieties are important for the passive permeation of the drug through the layers of lipids making up the membrane. In this talk I will present the computational methodology that we employ to test this hypothesis. In summary, the permeation of the drugs dyclonine (an aliphatic amine) and sodium phenylbutyrte (a carboxylic acid) through lipid bilayers composed of DPPC lipids is modeled through atomistic molecular dynamics simulations. The detailed dynamics of the drugs is then mapped to a process of one-dimensional diffusion in a potential. Additionally allowing for protonation/deprotonation events to take place during the permeation process,we explore how the proton exchange kinetics modifies the inward drug current. Our analysis offers a mechanistic explanation for the observed prevalence of aliphatic amines and carboxylic acids among drugs. Understanding the physicochemical factors controlling the passive permeation of aliphatic amines and carboxylic acids across the lipid bilayer may facilitate the prediction of synergistic drug pairs whose joint efficacy is larger than the sum of their separate efficacies [3]. This may lead to the rational design of drug pairs that "help" each other to cross the cell membrane.

REFERENCES [1] D. T. Manallack, R. J. Prankerd, G. C. Nassta, O. Ursu, T. I. Oprea, D. K. Chalmers, "A Chemogenomic Analysis ofIonization Constants – Implications for Drug Discovery," ChemMedChem 8, 242-255 (2013).[2] D. T. Manallack, M. L. Dennis, M. R. Kelly, R. J. Prankerd, E. Yuriev, and D. K. Chalmers, "The Acid/Base Profile ofthe Human Metabolome and Natural Products," Molecular Informatics 32, 505-515 (2013).[3] M. Çokol, H. N. Chua

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