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Evaluating the relative free energy of hydration of new thrombin inhibitor candidates using the finite difference thermodynamic integration (FDTI) method
Author(s) -
Guimarães Cristiano Ruch Werneck,
Bicca de Alencastro Ricardo
Publication year - 2001
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.1701
Subject(s) - benzamidine , thrombin , solvation , chemistry , serine protease , orthogonality , computational chemistry , thermodynamics , physics , mathematics , enzyme , protease , organic chemistry , molecule , platelet , geometry , immunology , biology
Thrombin is a serine protease involved in blood coagulation. Since thrombin inhibitors appear to be effective in the treatment and prevention of thrombotic and embolic disorders, considerable attention has been focused on the structure and interactions of the enzyme. In this work, we calculated the relative free energies of hydration of the new thrombin inhibitor candidates, p ‐substituted derivatives of benzamidine, a well‐known noncovalent thrombin inhibitor. We used molecular dynamics and the finite difference thermodynamic integration (FDTI) algorithm within the Discover program of MSI. We have shown that the orthogonality problem that occurs in the calculation of intraperturbed‐group contributions to the free energy is treated adequately by the FDTI method. We have also shown that problems of singularity and convergence in free energy calculations can be properly solved using this method. To conclude, the calculated free energies of hydration gave the following order of solvation for the candidates: p ‐(2‐oxo‐1‐propyl)benzamidine > p ‐methylbenzamidine > p ‐ethylbenzamidine > p ‐(1‐propyl)benzamidine > benzamidine. © 2001 John Wiley & Sons, Inc. Int J Quantum Chem, 2001