The Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects

Arylglyoxals in synthesis of heterocyclic compounds.

Isoxazole ring as a useful scaffold in a search for new therapeutic agents.

The critical issues in docking include the prediction of the correct binding pose and the accurate estimation of the corresponding binding affinity. Different docking methodologies have all been successful in reproducing the crystallographic binding modes but struggle when predicting the corresponding binding affinities. The aim of this work is to evaluate the performance of the MM-GB/SA rescoring of docking poses in structure-based lead optimization. To accomplish that, a diverse set of pharmaceutically relevant targets, including CDK2, FactorXa, Thrombin, and HIV-RT were selected. The correlation between the MM-GB/SA results and experimental data in all cases is remarkable. It even qualifies this approach as a more attractive alternative for rank-ordering than the Free Energy Perturbation and Thermodynamic Integration methodologies because, while as accurate, it can handle more structurally dissimilar ligands and provides results at a fraction of the computational cost. On the technical side, the benefit of performing a conformational analysis and having an ensemble of conformers to represent each ligand in the unbound state during the MM-GB/SA rescoring procedure was investigated. In addition, the estimation of conformational entropy penalties for the ligands upon binding, computed from the Boltzmann distribution in water, was evaluated and compared to a commonly used approach employed by many docking scoring functions.

MM-GB/SA rescoring of docking poses in structure-based lead optimization.

Covering: July 1998 to the end of July 1999. Previous review: J. Chem. Soc., Perkin Trans. 1, 1999, 641.

The synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones

Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety.

Structural Modification of an Orally Active Thrombin Inhibitor, LB30057: Replacement of the D-Pocket-binding Naphthyl Moiety

Benzylamine-based selective and orally bioavailable inhibitors of thrombin

The synthesis and biological activity of a series of new 1β-methylcarbapenems Scheme 5 , Figure FX1 Download : Download high-res image (133KB) Download : Download full-size image Scheme 5 . Reagents and reaction conditions: (i) DIPEA, CH3CN, rt, 1 h; (ii) Zn, phosphate buffer (pH 6.0), THF, rt, Diaion HP-20; (iii) iodomethane, acetone, rt; (iv) iodoacetamide, acetone, rt. containing 5′-isoxazolopyrrolidin-3′-ylthio derivatives as C-2 side chain are described. Most compounds exhibited potent and well-balanced antibacterial activity as well as high stability to DHP-I comparable to that of meropenem. Scheme 5 , Figure FX1 showed the best combination of antibacterial activity and stability to DHP-I, respectively.

Chang Yong Hong

Papers

Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety.

Structural Modification of an Orally Active Thrombin Inhibitor, LB30057: Replacement of the D-Pocket-binding Naphthyl Moiety

Benzylamine-based selective and orally bioavailable inhibitors of thrombin

Synthesis and Antibacterial Activity of New Carbapenems Containing Isoxazole Moiety.