Strategies toward predicting peptide cellular permeability from computed molecular descriptors

Abstract

The therapeutic efficacy of an orally administered drug is dictated not only by its pharmacological properties such as potency and selectivity, but also its pharmacokinetic properties such as its access to the site of activity. Thorough evaluation of the physicochemical and biological barriers to drug delivery is essential to the selection and successful development of drug candidates. We have demonstrated previously that cellular permeability, as a primary component of drug delivery, is principally dependent upon the desolvation potential of the polar functionalities in the molecule and, secondarily, upon the solute lipophilicity [Conradi, R.A., Hilgers, A.R., Ho, N.F.H., Burton, P.S. (1992). The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 473-479]. Increasingly sophisticated computational methods are becoming available for describing molecular structural features proposed to correlate with such molecular physicochemical determinants of permeability. Herein we examine the relationships of various computationally derived molecular geometric descriptors for a set of peptides and peptidomimetics, in the context of experimentally measured hydrogen-bond potentials and lipophilicities, with their cellular permeabilities. These descriptors include molecular volume, polar and non-polar surface areas and projected molecular cross-sectional areas. Particular attention is paid to the roles of solvation treatments and other computational factors in descriptor generation, deconvolution of cellular transport mechanisms and statistical analyses of the resulting data for the development of valid, structure-based and mechanistically meaningful models of cellular permeability. No significant correlation of cellular permeability with computed descriptors was found. This was primarily because of our inability to identify surrogates for hydrogen-bond desolvation potential for the solutes from among these descriptors.

An NMR study of conformations of substituted dipeptides in dodecylphosphocholine micelles: Implications for drug transport

“…Estimations of solute size from the molecular weight of the analogues and from dynamic volume were also performed. The details of the synthesis, Caco‐2 transport, and partition experiments, as well as the solute size computations, have been reported elsewhere 12. Results from some of these earlier experiments will be used in interpreting the implications of the spectroscopic data herein described.…”

“…The dipeptide analogues used in this study were synthesized in our labs using standard solution‐phase methods as previously described 2. Details of the synthesis and purification of the dipeptides are reported separately 12…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…In aqueous solutions, the hydration of pendent H-bonding donor or acceptor groups retards the permeation of a drug molecule through biological membranes [179,180,182]. The predictable formation of certain intramolecular motifs has a significant influence on the ability of the molecule to engage in intermolecular hydrogen bonding [183] and affects molecular properties including biological and pharmacological activities.…”

An atomistic model of passive membrane permeability: application to a series of FDA approved drugs

“…In brief, for any given compound, we attempt to identify the conformation that will minimize the free energy cost of transferring the compound from water (high dielectric) to the interior of the membrane (low dielectric). In a practical sense, we identify this conformation by searching for the lowest energy conformation using a molecular mechanics (MM) energy function consisting of the OPLS all-atom force field [22,23] and a GB/SA (generalized Born/surface area) implicit solvent model [24] with parameters tuned to represent chloroform [25] as a mimic of the hydrophobic interior of the membrane [26]. The transfer free energy of this conformation between water and chloroform is then used as a measure of its relative passive membrane permeability.…”