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Antiviral Agents and Rational Drug Design
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
By understanding the binding of the substrate, chemists were able to propose a mechanism for the hydrolysis reaction. It was discovered to involve proton donation from an activated water molecule, facilitated by the negatively charged Asp-151 and formation of an endocyclic sialosyl cation TS intermediate. Then sialic acid is formed and released. This proposed mechanism was supported by kinetic isotope studies, which indicate an SN1 nucleophilic substitution and NMR spectroscopy, a technique used to study the change in conformation of the substrate, showed that sialic acid is released as the α-anomer; consistent with an SN1 mechanism. Also, site-directed mutagenesis showed that replacing the charged amino acids Arg-151 with lysine and Glu-227 by aspartate, so that stabilisation of the intermediate is repressed, activity of the enzyme is lost.
Application of Bioresponsive Polymers in Gene Delivery
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Tamgue Serges William, Drashti Pathak, Deepa H. Patel
The ATP molecule is the most abundant nucleotide in the body and is obtained by different processes such as oxidative phosphorylation in mitochondria, a reaction during which, one molecule of glucose gives two molecules of ATP which later are hydrolyzed in ADP (adenosine diphosphate). That hydrolysis reaction is responsible for the energy supply required to maintain metabolisms such as muscle contraction, active transport, and glycolysis.
Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Introduction. Phase I biotransformations of drugs consist primarily of oxidations, hydrolyses, and reductions. Insofar as antiepileptic drugs are concerned, oxidations are the most important biotransformation pathways involved. Reductions are of very limited importance, and only one hydrolysis reaction will be discussed.
Toward a better understanding of metabolic and pharmacokinetic characteristics of low-solubility, low-permeability natural medicines
Published in Drug Metabolism Reviews, 2020
Jie Yang, Kailing Li, Dan He, Jing Gu, Jingyu Xu, Jiaxi Xie, Min Zhang, Yuying Liu, Qunyou Tan, Jingqing Zhang
Some substantial progress has been made in the last decades. So far, only 16 LLNMs have been documented about some metabolic and/or pharmacokinetic characteristics by retrieving their data from the available worldwide database. For disputed NMs, only the drug having the actual values of D0 and Log P documented in the references were included in this review. The solubility, permeability, molecular structure, and relationships of LLNMs are presented. The rules of structure-based metabolic reactions occurring in the intestine/liver are investigated. The hydrolysis reaction occurring in the intestine receives special attention. LLNMs are catalyzed into metabolites by enzymatic systems produced by intestinal epithelial cells and bacteria. Metabolism may result in activation, inactivation, partial activation, partial inactivation, and toxicity by LLNMs. Drug–drug interactions (DDIs) via metabolic enzyme modulation are assessed. The cellular and bodily pharmacological activities, as well as the in vivo pharmacokinetic behaviors of LLNMs are summarized. The pharmacodynamics and pharmacokinetics of LLNMs may be influenced by changing metabolism through using nanotechnology and nanosystems, in combination with suitable administration route and dosage. Deep insights into the differences in structural, physicochemical, metabolic, kinetic, and bioactive characteristics may help pharmacists and physicians to individualize economic and rational therapeutic regimens for LLNM treatment.
Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
Published in mAbs, 2020
Bradley N. Spatola, Alana G. Lerner, Clifford Wong, Tracy dela Cruz, Megan Welch, Wanchi Fung, Maria Kovalenko, Karolina Losenkova, Gennady G. Yegutkin, Courtney Beers, John Corbin, Vanessa B. Soros
CD39 is reported to have broad NTPase and NDPase specificities,39,40 so the rate of purine and pyrimidine nucleotide substrate hydrolysis was compared using a melanoma cell line (SK-MEL-28) that endogenously expresses CD39. Inorganic phosphate, Pi, a product of the CD39-mediated hydrolysis reaction converting ATP to ADP and AMP, was kinetically monitored. Figure 1a shows the initial velocity of Pi release plotted against substrate concentration with the data fit to a Michaelis-Menten model (Equation 1). NTP and ADP substrates were hydrolyzed with a similar maximal velocity (Vmax), and the Michaelis constant (Km) fell within a range of approximately 30 to 70 µM (Table S1). The Vmax and Km for AMP, which is hydrolyzed by endogenously expressed CD73 on SK-MEL-28 cells, were greater than that of the CD39-hydrolyzed substrates. When higher substrate concentrations are tested, nucleotide hydrolysis follows a substrate inhibition model41 (Figure S1). Kinetic enzymatic assessment of other CD39+ primary cells and cell lines confirmed Km for ATP catabolism ranges from approximately 10–200 µM2 (Table S2), and that Vmax correlated (Pearson r = 0.93, p < .001) with CD39 expression levels (Figure S2).
Gut microbiota: what is its place in pharmacology?
Published in Expert Review of Clinical Pharmacology, 2019
Aleksandra Tarasiuk, Jakub Fichna
The relationship between the therapeutic action and the GI microbiota has also been demonstrated for flavonoids – plant therapeutic compounds with primarily antioxidant effects. They are recommended in the prevention of cancer, atherosclerosis, heart and liver diseases. Both those given with diet and in the form of pharmacological preparations often occur in the form of inactive glycosides and to obtain their active formula, i.e. aglycone, a hydrolysis reaction should be carried out. Flavonoids undergo hydrolysis primarily in the intestine, in the presence of enzymes secreted by GI bacteria. The most popular flavonoids with clinical importance include diosmin, hesperidin, silymarin, as well as soy isoflavones, recommended in the prevention of menopause. Numerous studies on GI microbiota indicate that bacterial enzymes can also catalyze such reactions as glucuronide hydrolysis, dehydroxylation, demethylation, reduction of binding dual, decomposition of the carbon ring to form phenolic acids followed by their decarboxylation and many others. All these reactions may contribute to flavonoid efficacy.