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Entropic Terms (entropic + term)
Selected AbstractsCan the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2002Sonja M. Schwarzl Abstract The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system. To examine possible improvement of scoring methods, we test the suitability of continuum electrostatics to account for solvation effects and use an ideal-gas entropy correction to account for the changes in the degrees of freedom of the ligand. The small observed root-mean-square deviation of 0.55 kcal/mol of the calculated relative to the experimental values indicates that the essentials of the binding process have been captured. Even though all six ligands make the same salt bridge and H-bonds to the protein, the electrostatic contribution varies among the ligands by as much as 2 kcal/mol. Moreover, although the ligands are rigid and similar in size, the entropic terms also significantly affect the relative binding affinities (by up to 2.7 kcal/mol). The present approach to solvation and entropy may allow the ranking of the ligands to be considerably improved at a cost that makes the method applicable to the optimization of lead compounds or to the screening of small collections of ligands. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1143,1149, 2002 [source] Synthesis, pharmacology, crystal properties, and quantitative solvation studies from a drug transport perspective for three new 1,2,4-thiadiazolesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2010German L. Perlovich Abstract A novel 1,2,4-thiadiazoles were synthesized. Crystal structures of these compounds were solved by X-ray diffraction experiments and comparative analysis of molecular conformational states, packing architecture, and hydrogen bonds networks were carried out. Thermodynamic aspects of sublimation processes of studied compounds were determined using temperature dependencies of vapor pressure. Thermophysical characteristics of the molecular crystals were obtained and compared with the sublimation and structural parameters. Solubility and solvation processes of 1,2,4-thiadiazoles in buffer, n -hexane and n -octanol were studied within the wide range of temperature intervals and thermodynamic functions were calculated. Specific and nonspecific interactions of molecules resolved in crystals and solvents were estimated and compared. Distribution processes of compounds in buffer/n -octanol and buffer/n -hexane systems (describing different types of membranes) were investigated. Analysis of transfer processes of studied molecules from the buffer to n -octanol/n -hexane phases was carried out by the diagram method with evaluation of the enthalpic and entropic terms. This approach allows us to design drug molecules with optimal passive transport properties. Calcium-blocking properties of the substances were evaluated. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3754,3768, 2010 [source] Thermodynamic and structural aspects of sulfonamide crystals and solutionsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2009German L. Perlovich Abstract The crystal structures of three sulfonamides with the general structure 4-NH2 -C6H4 -SO2NH-C6H4/3 -R (R,=,4-Et; 4-OMe; 5-Cl-2-Me) have been determined by X-ray diffraction. On the basis of our previous data and the results obtained a comparative analysis of crystal properties was performed: molecular conformational states, packing architecture, and hydrogen bond networks using graph set notations. The thermodynamic aspects of the sulfonamide sublimation process have been studied by investigating the temperature dependence of vapor pressure using the transpiration method. A regression equation was derived describing the correlation between sublimation entropy terms and crystal density data calculated from X-ray diffraction results. Also correlations between sublimation Gibbs energies and melting points, on the one hand, and between sublimation enthalpies and fusion enthalpies at 298 K, on the other hand, were found. These dependencies give the opportunity to predict sublimation thermodynamic parameters by simple thermo-physical experiments (fusion characteristics). Solubility processes of the compounds in water, n -hexane, and n -octanol (as phases modeling various drug delivery pathways and different types of membranes) were investigated and corresponding thermodynamic functions were calculated as well. Thermodynamic characteristics of sulfonamide solvation were evaluated. For compounds with similar structures processes of transfer from one solvent to another one were studied by a diagram method combined with analysis of enthalpic and entropic terms. Distinguishing between enthalpy and entropy, as is possible through the present approach, leads to the insight that the contribution of these terms is different for different molecules (entropy- or enthalpy-determined). Thus, in contrast to interpretation of only the Gibbs energy of transfer, being extensively used for pharmaceuticals in the form of the partition coefficient (log,P), the analysis of thermodynamic functions of the transfer process provides additional mechanistic information. This may be important for further evaluation of the physiological distribution of drug molecules and may provide a better understanding of biopharmaceutical properties of drugs. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4738,4755, 2009 [source] Water Accessibility to the Binding Cleft as a Major Switching Factor from Entropy-Driven to Enthalpy-Driven Binding of an Alkyl Group by Synthetic ReceptorsCHEMISTRY - AN ASIAN JOURNAL, Issue 5 2010Sayaka Matsumoto Abstract Free energy, enthalpy, and entropy changes in the binding of alkyl pyridines to water-soluble zinc porphyrin receptors with varying accessibility of water to the binding cleft were determined to explain why the driving force of hydrophobic effects is enthalpic in some occasions and entropic in others. Zinc porphyrins bearing four alkyl pillars with terminal solubilizing poly(oxyethylene) (POE) chains of molecular weight of 750 (1), with eight alkyl pillars with terminal solubilizing POE chains of molecular weight of 350 (3), and with eight alkyl pillars with POE of molecular weight of 750 (4) had a binding cleft with decreasing water accessibility in this order as revealed by binding selectivity of imidazole/pyridine. Although all these porphyrins showed that the free energy of binding (,,Go) increases linearly as the alkyl group of the guest is lengthened (,,Go per CH2 was 2.6, 2.8, and 2.6,kJ,mol,1 for 1, 3, and 4, respectively), the origin of the free energy gain was much different. Receptor 1 with the most hydrophilic binding site bound the alkyl group by an enthalpic driving force (4-pentylpyridine favored over 4-methylpyridine by ,,Ho=,16.4,kJ,mol,1), while receptor 4 with the most hydrophobic binding site by an entropic driving force (4-pentylpyridine favored over 4-methylpyridine by ,,So=39.6,J,K,1,mol,1). Receptor 3 showed intermediate behavior: both enthalpic and entropic terms drove the binding of the alkyl group with the enthalpic driving force being dominant. The binding site of the four-pillared receptor (1) is open and accessible to water molecules, and is more hydrophilic than that of the eight-pillared receptor (4). We propose that the alkyl chains of 1 are exposed to water to produce a room to accommodate the guest to result in enthalpy-driven hydrophobic binding, whereas 4 can accommodate the guest without such structural changes to lead to entropy-driven hydrophobic binding. Therefore, accessibility of water or exposure of the binding site to the water phase switches the driving force of hydrophobic effects from an entropic force to an enthalpic force. [source] | ||||||||||