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A molecular dynamics study on liquid 1‐octanol. Part 3. Evaluating octanol/water partition coefficients of novel thrombin inhibitors via free‐energy perturbations
Author(s) -
Fernandes De Oliveira César Augusto,
Werneck Guimarães Cristiano Ruch,
De Mello Heloisa,
Echevarria Aurea,
De Alencastro Ricardo Bicca
Publication year - 2005
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.20485
Subject(s) - benzamidine , partition coefficient , chemistry , molecular dynamics , octanol , bioavailability , thrombin , computational chemistry , enzyme , organic chemistry , platelet , bioinformatics , immunology , biology
Abstract Thrombin 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 P o/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 P o/w for the benzamidine derivatives. To examine the reliability of the method, log P o/w values for Bz and PMBz were determined experimentally. Experimental log P o/w of −1.02 and −0.89 were obtained for Bz and PMBz, and theoretical log P o/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 P o/w above zero and into a region where reasonable oral absorption might be expected. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005