title: Thrombin inhibition by novel benzamidine derivatives: a free-energy perturbation study.
abstract: Thrombin is a serine protease responsible for 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 this enzyme. In this work, to evaluate the relative free energies of hydration and binding to thrombin for some benzamidine derivatives, we used the finite difference thermodynamic integration (FDTI) algorithm within the Discover program of MSI. By this method, two possible orders of hydration for the candidates were obtained: p-amidinophenylpyruvate > p-(2-oxo-1-propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > p-(1-propyl)benzamidine > benzamidine and p-amidinophenylpyruvate > p-(2-oxo-1-propyl)benzamidine > p-methylbenzamidine > p-ethylbenzamidine > benzamidine > p-(1-propyl)benzamidine. We also obtained the following order for thrombin binding: p-(2-oxo-1-propyl)benzamidine > p-ethylbenzamidine > p-(1-propyl)benzamidine > p-methylbenzamidine > benzamidine > p-amidinophenylpyruvate.
authors.affiliation: Physical Organic Chemistry Group, Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, CT, Bloco A, lab. 609, Brazil. cris@ramana.chem.yale.edu
authors.forename: Cristiano Ruch Werneck
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Ricardo
authors.initials: R
authors.lastname: Bicca de Alencastro
mesh_terms: D001550:Benzamidines / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*; D013816:Thermodynamics; D013917:Thrombin / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D001550:Benzamidines; D015842:Serine Proteinase Inhibitors; D014867:Water; D013917:Thrombin