A summary of drugs targeting enzymes

Enzymes act as biological catalysts in living organisms, by regulating the rate of chemical reactions, without themselves being altered in the process. Enzymes act as a target for drugs for the desired therapeutic effect, which are thereby called biological targets. Enzymes offer unique opportunities for drug design that are not available to cell surface receptors, nuclear hormone receptors, ion channels, transporters. Drugs that function as enzyme inhibitors constitute a significant portion of the orally bioavailable therapeutic agents that are in clinical use today. Likewise, much of drug discovery and development efforts at present are focused on identifying and optimizing drug candidates that act through inhibition of specific enzyme targets. Drugs acting on enzymes can either inhibit them or activate them. Inhibition of enzymes is a strategy which is more commonly used rather than activation of enzymes. 47% of all current drugs inhibit their enzyme targets. Enzyme activity can not only be inhibited; it can also be accelerated through biochemical modification of the enzyme. In this manuscript, the authors provide a system-wise summary of drugs acting on enzymes, microsomal enzymes targeted by drug and newly approved drugs acting on enzymes.

Genotoxic and Mutagenic Activity of Particulate Matter Gathered in a High Emitter Automotive Diesel Engine Operated With Different Palm Oil-Derived Biofuels

The need to substitute fossil fuels with energy alternatives has favored the development of biodiesel and green diesel, which generate less amount of particulate matter (PM), but their biological reactivity is unknown, an important factor of quality and risk. Therefore, the genotoxicity and mutagenicity potential of PM emitted by the combustion of mixtures of green diesel and palm biodiesel with petroleum diesel has been evaluated; 10% palm biodiesel (B10), 10% and 30% green diesel (HVO10 and HVO30) and ultralow sulfur diesel (ULSD) were subjected to combustion at two engine operating speeds: 1890 and 2410 rpm. From each PM sample, the organic fraction was extracted to evaluate the mutagenicity with the Ames test in the presence and absence of microsomal enzymes, and the genotoxicity with the alkaline comet assay, while in the Ames test, concentrations of equivalent 3, 1.5, and 0.8 μg of PM/µl were considered; in the comet assay, equivalent 3.1, 6.3, and 12.5 μg of PM/µl were tested. The organic fraction of the PM from the ULSD was the least genotoxic and mutagenic. In contrast, the organic fraction of the PM of HVO30 showed the highest genotoxic and mutagenic activity (p < 0.05). Although the genotoxic potential of PM generated at 1890 rpm, low speed, was slightly higher, no relationship was found regarding the engine operating speed. The results of this investigation show that the fuel extraction method and the mixture with the petroleum diesel affect the quality of the PM and, therefore, its biological activity. Consequently, the physicochemical monitoring of the PM should be complemented with biological procedures to evaluate the quality of alternative fuels and protect the environmental health.

TOXICITY AND HAZARD OF NEUROPARALYTIC ACTION OF FIRE-RESISTANT TURBINE OILS BASED ON TRIARYL PHOSPHATES

The paper presents the results of assessing the toxicity and danger of the development of neuroparalytic effect of fire-resistant turbine oils «Turbomas», «T-94» and «T-95» based on triaryl phosphates. According to the toxicity parameters, the studied oils are low-toxic substances, exhibit weakly expressed cumulative properties, do not irritate the skin and mucous membranes, penetrate through intact skin, and increase the activity of microsomal enzymes, when injected into the stomach and abdominal cavity. The study of the neuroparalytic action of oils «Turbomas», «T-94» and «T-95» did not reveal the presence of clinical and morphological signs of disorders of the neuromuscular apparatus in animals, which makes it possible to exclude the possibility of neuroparalytic action in persons in contact with the studied oils.

Effects of a rifampicin pre-treatment on linezolid pharmacokinetics

Linezolid is an oxazolidinone antibiotic that effectively treats methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Since rifampicin induces other antibiotic effects, it is combined with linezolid in therapeutic regimes. However, linezolid blood concentrations are reduced by this combination, which increases the risk of the emergence of antibiotic-resistant bacteria. We herein demonstrated that the combination of linezolid with rifampicin inhibited its absorption and promoted its elimination, but not through microsomal enzymes. Our results indicate that the combination of linezolid with rifampicin reduces linezolid blood concentrations via metabolic enzymes.