A molecular dynamics study on liquid 1‐octanol. Part 3. Evaluating octanol/water partition coefficients of novel thrombin inhibitors via free‐energy perturbations

Abstract

AbstractThrombin inhibition is an important strategy for the treatment of thrombotic and embolic disorders. Despite high in vitro affinity for the enzyme, synthetic thrombin inhibitors have limited oral bioavailability due to low intestinal permeability. In a previous work, we obtained the following order for thrombin binding by using molecular dynamics (MD) simulations and the finite difference thermodynamic integration (FDTI) method: p‐(2‐oxo‐1‐propyl)benzamidine (POPBz) > p‐ethylbenzamidine (PEBz) > p‐(1‐propyl)benzamidine (PPBz) > p‐methylbenzamidine (PMBz) > benzamidine (Bz). As the octanol/water partition coefficient (log Po/w) is a thermodynamic property that may be related to drug transfer across biological membranes, we now turn our attention to the calculation by the FDTI method of relative log Po/w for the benzamidine derivatives. To examine the reliability of the method, log Po/w values for Bz and PMBz were determined experimentally. Experimental log Po/w of −1.02 and −0.89 were obtained for Bz and PMBz, and theoretical log Po/w of −0.12, −0.01, and −1.00 were obtained for PEBz, PPBz, and POPBz. Thus, we improved the hydrophobicity of Bz by adding the methyl, ethyl, propyl, and 2‐oxo‐propyl groups, but further substitutions should be conducted to raise log Po/w above zero and into a region where reasonable oral absorption might be expected. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005