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Targeting the Nervous System
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Anticholinesterase drugs inhibit the active site of acetylcholinesterase reversibly or irreversibly, depending on the interactions with the active site. The two main groups of anticholinesterases include carbamates and organophosphorus compounds. The lead compound for the carbamate inhibiters was sourced from the natural product physostigmine, which was discovered in 1864 as a product from the poisonous calabar bean from West Africa; structure determined in 1925. This compound is still used clinically to treat glaucoma. SAR studies show that the carbamate group is essential to the activity, the benzene ring is important, and the pyrollidine nitrogen is ionised at blood pH; crucial for binding to anionic residues in the active site. The carbamate group is crucial for the inhibitory properties of physostigmine. The mechanism for hydrolysis produces a stable carbonyl intermediate which is the rate-determining step. Molecular structures for some of these compounds are given in Figure 6 of the Supporting Material∗. Due to serious side-effects, its medical uses are limited, so analogues have been made that retain these important features.
Research Quality Assurance
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
The major qualifications one looks for in clinical auditors [12] and monitors are formal degree in a scientific discipline and the ability to interact and deal effectively with people. Most of the personnel utilized in clinical auditing within the pharmaceutical industry have at least a B. S. degree in a relevant scientific discipline and several years' experience in a laboratory or hospital environment. The need to deal effectively with people is obvious. The clinical auditor is in a position where tact and strong negotiating skills are necessary to get medical monitors and/or clinical investigators to correct deficiencies observed during the course of an audit. While entry-level auditors may have strong backgrounds in science and human relations, there is still a need to train these individuals in the techniques of auditing as well as the overall pharmaceutical research process itself. While the auditor or monitor may only be directly involved in the final rate-determining step of the drug development process, it is important that he or she understand what goes into the development of the drug prior to studying it in the human model.
Kinetics Part 2 Application of Rate Laws and Rate Variables to Reaction Mechanisms
Published in Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk, Survival Guide to General Chemistry, 2019
Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk
Reaction mechanisms may be composed of only a single step. However, in a complete multi-step reaction, one of the steps is very often much slower than the rest of the steps. (This is the molecular equivalent of a “bottleneck” in a manufacturing plant.) The slowest chemical step in a complete multi-step mechanism is termed the rate determining step (abbreviated r.d.s.).
The first activation study of the β-carbonic anhydrases from the pathogenic bacteria Brucella suis and Francisella tularensis with amines and amino acids
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Andrea Angeli, Sonia Del Prete, Mariana Pinteala, Stelian S. Maier, William A. Donald, Bogdan C. Simionescu, Clemente Capasso, Claudiu T. Supuran
In the first step, a zinc-bound hydroxide species of the enzyme with a strong nucleophilicity, attacks the CO2 substrate, which is weakly bound in a hydrophobic pocket nearby, being optimally orientated for the hydration reaction to occur by the attack of the zinc hydroxide nucleophile (Equation 1)8. In the next step of the process, the formed bicarbonate in the hydration reaction is replaced by an incoming water molecule, leading to the formation of an acidic enzymatic species, EZn2+—OH2 (Equation 1). In order to regenerate the zinc hydroxide species, a proton must be transferred from the Zn(II)-bound water molecule to the external medium (Equation 2). This is also the rate-determining step of the entire catalytic cycle8–10. In the presence of activators (A in Equation 3), this rate-determining step is facilitated by an additional proton release pathway, which involves the activator A bound within the enzyme active site. It should be noted that all CAAs known to date possess in their molecule protonatable moieties of the amine, carboxylate or imidazole type, with pKa values in the range of 5–88–10.
A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017
Published in Expert Opinion on Therapeutic Patents, 2018
Vincenza Andrisano, Marina Naldi, Angela De Simone, Manuela Bartolini
Despite genes encoding for BuChE and AChE are different, BuChE shows a 65% amino-acid sequence homology, similar molecular form and active center structure with AChE [6]. In both cholinesterases, substrate hydrolysis takes place at the bottom of a 20 Å deep gorge where the so-called catalytic triad formed by a serine, a glutamate, and a histidine residue (Ser198, Glu325, and His438, for human BuChE) is located [7]. However, despite structural similarity, differences in the rate-limiting step have been disclosed: in BuChE the rate limiting-step is the substrate acylation while for AChE the rate-determining step is the substrate deacylation [8]. Moreover, the rate of hydrolysis of the neurotransmitter ACh differs between the two cholinesterases being BuChE less efficient in hydrolyzing ACh; on the other hand, thanks to the larger gorge [9], BuChE can accommodate bulkier substrates (and inhibitors) such as the non-physiological substrate butyrylcholine (BCh). Finally, catalytic activity at the active site is influenced by a further binding site located at the entrance of the gorge and defined as ‘peripheral anionic site’ (PAS). PAS has been extensively characterized in the case of AChE, while only limited studies have been carried out to characterize the BuChE’s PAS role [10].
The impact of exposure route for class-based compounds: a comparative approach of lethal toxicity data in rodent models
Published in Drug and Chemical Toxicology, 2018
Yu Wang, Shuo Wang, Xiao N. Feng, Li C. Yan, Shan S. Zheng, Yue Wang, Yuan H. Zhao
However, the toxicity of a compound is determined by the concentration/amount at the target site(s), and not by the concentration in the blood. The concentration at the target site is not only dependent upon the absorption rate, but also upon the distribution rate. The toxicity of a compound which is determined by the concentration at the target site(s) is closely related to the rate determining step. At least, three situations will influence a toxic response at a target site. If the distribution rate (kD) is very fast for a chemical, the absorption rate will be the determining step for the concentration at the target site. A greater absorption rate indicates a higher concentration at the target site, leading to higher toxicity of the chemical from the exposure routes (i.e., Region 1 (R1) in Figure 1). On the other hand, if distribution rate is slow, the concentration of a chemical at the target site will be independent of the absorption rate, leading to similar toxicities between exposure routes (Region 3 (R3) in Figure 1). If the distribution rate is close to the absorption rate, both absorption and distribution rates have significance to the toxicity of the chemical in mammals (Region 2 (R2) in Figure 1).