New insights into human farnesyl pyrophosphate synthase inhibition by second-generation bisphosphonate drugs.

Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values. However, there is a lack of information explaining this similar final inhibitory potency. Although different residues have been identified in the stabilization of the R2 side chain of 2G-BPs into the active site, similar free binding energies were obtained that highlighted a similar stability of the ternary complexes, which in turns justified the similar IC50 values reported. Free binding energy calculations also demonstrated that the union of 2G-BPs to the active site were 38 to 54 kcal mol-1 energetically more favourable than the union of the natural substrate, which is the basis of the inhibition potency of the hFPPS activity.

Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor.

DNA nucleobases undergo non-enzymatic glycation to nucleobase adducts which can play important roles in vivo. In this work, we conducted a comprehensive experimental and theoretical kinetic study of the mechanisms of formation of glyoxal-guanine adducts over a wide pH range in order to elucidate the molecular basis for the glycation process. Also, we performed molecular dynamics simulations to investigate how open or cyclic glyoxal-guanine adducts can cause structural changes in an oligonucleotide model. A thermodynamic study of other glycating agents including methylglyoxal, acrolein, crotonaldehyde, 4-hydroxynonenal and 3-deoxyglucosone revealed that, at neutral pH, cyclic adducts were more stable than open adducts; at basic pH, however, the open adducts of 3-deoxyglucosone, methylglyoxal and glyoxal were more stable than their cyclic counterparts. This result can be ascribed to the ability of the adducts to cross-link DNA. The new insights may contribute to improve our understanding of the connection between glycation and DNA cross-linking.

FT-IR study of pyridoxamine 5' phosphate.

Aqueous solutions of pyridoxamine 5' phosphate (PMP) at several pH conditions have been studied using FT-IR spectroscopy using the attenuated total reflection (ATR) technique. In spite of the strong intense OH stretching and bending bands of water, most of the vibrational structure of solute can be observed from 900 to 1500 cm(-1). With increasing pH, very intense changes in the spectra have been observed due to concentration changes of the hydrogen bonded species. Spectra of the different ionic species have been calculated from the mathematical fitting of experimental absorption spectra as a function of pH. Spectra are characterized by the presence of broad band-like structures in the 2400-3500 cm(-1) region, with extended continua that indicate very large proton polarizability of hydrogen bonds. Contributions of the phosphate group to the total absorption have been analyzed by comparison with pyridoxamine spectra.

Electrostatic and structural similarity of classical and non-classical lactam compounds.

Various electrostatic and structural parameters for a series of classical and non-classical beta-lactams were determined and compared in order to ascertain whether some specific beta-lactams possess antibacterial or beta-lactamase inhibitory properties. The electrostatic parameters obtained, based on the Distributed Multipole Analysis (DMA) of high-quality wavefunctions for the studied structures, suggest that some non-classical beta-lactams effectively inhibit the action of beta-lactamases. As shown in this work, such electrostatic parameters provide much more reliable information about the antibacterial and inhibitory properties of beta-lactams than do structural parameters.

Alkaline hydrolysis of cefotaxime. A HPLC and 1H NMR study.

A kinetic study on the alkaline hydrolysis of cefotaxime at pH 10.5 and 37 degrees C has been carried out by using HPLC and 1H NMR. The main resulting degradation products have been isolated and identified. These include, apart from the well-known deacetylcefotaxime, the exocyclic methylene derivative, the 7-epimer of cefotaxime and the 7-epimer of deacetylcefotaxime. The kinetic constants involved in the process have been determined and according to the experimental results the attack of the hydroxyl group on the ester function bonded to the 3'-carbon is the fastest step in the proposed kinetic scheme. It should be emphasized that the base-catalyzed epimerization of the hydrogen at the 7 position clearly depends on the presence of a good electron-withdrawing group at C(3'). On the other hand, no hydrolysis of the amide at position 7 was detected.