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A Brief Background
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Understanding electrons is essential to chemistry. In a reaction, chemical bonds must be broken: this may be a heterolytic cleavage, where two electrons in the bond move to one species to form ions, or a homolytic cleavage, where the pair of electrons are shared to produce free radicals. In organic chemistry, the movement of electrons is shown with curly arrows to produce organic reaction mechanisms, which will feature later in the text. Since reactivity is the movement of electrons to break weak bonds and make new, stronger bonds, it is possible to predict how an organic reaction mechanism will proceed. For two reacting molecules, identify where the electrons are coming from. This molecule is termed the nucleophile—a negatively charged ion, or neutral molecule with a lone pair of electrons which are donated to form a covalent bond. The electrons are received by the electron-deficient molecule called an electrophile. Whether a given molecule will react as a nucleophile or an electrophile depends on the functional groups that are present.
Kinetics Part 1
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
Kinetics is the study of rates of complete reactions by mathematical and experimental analysis to determine reaction mechanisms. A reaction mechanism is a description of the bonding events that occur along the pathway reactants follow to form products.
Simple Receptor-Ligand Interactions
Published in John C. Matthews, Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
Reaction Mechanism 1 represents a chemical reaction (or more accurately a chemical interaction) that, mathematically, is not different from any other type of chemical reaction. For example, the dissociation of an acid to form a proton and an acid anion is expressed as
Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Juliusz Maksymilian Walczak, Dorota Iwaszkiewicz-Grześ, Michalina Ziomkowska, Magdalena Śliwka-Kaszyńska, Mateusz Daśko, Piotr Trzonkowski, Grzegorz Cholewiński
For A1, A8, A11, and A14 cases, 2.0 equivalents of tertiary amine (DIPEA) were applied due to standard procedure present in the literature35. However, in most cases only 1.0 equivalent was utilised on account of reaction mechanism. Initially, each reaction was carried out in a manner consistent with the reaction mechanism, but the one proposed in the literature was also studied. Differences in the base amounts may happen due to the high stability of salt formed upon MPA and amine dissolution. Increasing the amount of DIPEA alters pH balance which affects the tendency of amine to react with activated MPA as it may less readily occur in protonated form. Base excess is believed to increase coupling rates and to disrupt hydrogen bonds responsible for conformation stabilisation which affects the availability of amino groups36. A3 was synthesised with individual quantities of base and activating agent used which were developed through the optimisation process. Due to the potential N-acyl 2-aminobenzo[d]-1H-imidazole isomerisation processes observed between annular and exocyclic nitrogen atoms, two products would occur. However, 1H NMR spectrum proved N-acylation at the exocyclic nitrogen as an additional peak close to 12 ppm was observed (one annular, one amide, and one phenolic protons all deshielded in the magnetic field). Isomerisation and tautomerisation phenomena may affect reaction outcomes, e.g. decreasing yields as for A3.
Peptide reactivity assays for skin sensitisation – scope and limitations
Published in Critical Reviews in Toxicology, 2022
Even when optimised by the amendments above, both the DPRA-cys and the kDPRA have significant limitations resulting from chemistry-potency applicability domain issues. Using a reactivity parameter alone to assign a chemical as a sensitiser or non-sensitiser (e.g. peptide depletion in the DPRA to assign S or NS), or to assign a potency classification (e.g. logkmax in the kDPRA to assign 1A or 1B/NS) is based on the implicit assumption that potency of a chemical is a single increasing function of its reactivity and of nothing else. The predictive performance of a reactivity assay depends on the extent to which this implicit assumption applies. As discussed earlier (Roberts 2021a) and as illustrated here by the example of phthalic and trimellitic anhydrides, for many chemicals potency is related to a combination of reactivity and hydrophobicity rather than reactivity alone. Furthermore, even when potency is dependent on reactivity alone, the degree of dependence varies according to the reaction mechanism.
Frontiers of metal-coordinating drug design
Published in Expert Opinion on Drug Discovery, 2021
Giulia Palermo, Angelo Spinello, Aakash Saha, Alessandra Magistrato
A clear understanding of the reaction mechanism by multi-scale simulations is instrumental to design small-molecules that covalently inhibit the enzyme. This is notable in the steroidal inhibitor exemestane (EXE) [111] or for characterizing the metal–ligand interaction underlying the inhibition mechanism of non-steroidal inhibitors, which have so far eluded a structural characterization by experimental means [110]. The third-generation of AR inhibitors (AI) shares a common azole moiety, which is believed to coordinate the heme iron atom. QM/MM MD simulations have provided insights into the possible binding mode of letrozole, a-third generation AI, to the AR’s active site (Figure 3B) [112]. In addition, these inhibitors were used to estimate the binding free-energy and dissociation free-energy barrier of letrozole to/from the metal center [112]. This study showed that the dissociation free-energy cost associated with the cleavage of the covalent bond with the Fe atom is comparable to that for traveling among the egress channels. Therefore, both aspects have to be considered in order to ameliorate the kinetic properties of such drugs.