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β-Lactams and Related Compounds as Antibacterials and β-Lactamase Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Ulrike Holzgrabe, Jens Schmitz
Recently (2017), the first cyclic boronic acid inhibitor, vaborbactam (RPX7009), in combination with meropenem was approved by the FDA (see FDA press release). As the DBO-type inhibitors, vaborbactam is a reversible inhibitor. Here the carbonyl function was replaced with a boron atom, which is nucleophilically attacked by the serine-OH of SBLs (see Fig. 8.10) and adopts in complex with KPC carbapenemase an acylation transition state binding mode with the carboxyl moiety located at the carboxyl binding pocket and the exocyclic boron oxygen occupying the oxyanion hole. In MBLs, vaborbactam complexes both Zn atoms (cf. Fig. 8.11). The amide moiety, which is in a similar position as in penicillins, shows a couple of interactions across the active site (Hecker et al., 2015) stabilizing the complex.
Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Ireen Denya, Sarel F. Malan, Jacques Joubert
AChE and BuChE share a 65% amino acid sequence homology and have similar molecular forms and active site structure (Allderdice et al., 1991). Early kinetic studies indicate that the active site of AChE contains two subsites, the esteratic and anionic subsites, corresponding to the catalytic and choline–binding pockets, respectively. The anionic active subsite interacts with the charged quaternary group of the choline moiety of acetylcholine (Augustinsson et al., 1950; Rosenberry, 2006). It contains the amino acids Trp 86, Tyr 133, Tyr 337 and Phe 338 and these bind the quaternary trimethylammonium choline moiety of the substrate mainly through π-cation interactions (Harel et al., 1993) positioning the ester optimally at the acylation site. The acyl pocket, responsible for substrate selectivity by preventing access of the larger choline esters is composed of Phe 295 and Phe 297. The oxyanion hole, Gly 121, Gly 122 and Ala 204, provides hydrogen bond donors that stabilise the tetrahedral transition state of the substrate (Ordentlich et al., 1998). Cationic substrates are not bound by a negatively charged amino acid in the anionic site, but by interaction of 14 aromatic residues that line the gorge leading to the active site (Colovic et al., 2013). Among the aromatic amino acids, Trp 84 is reported to be critical and not substitutable (Tougu, 2001). The esteratic subsite or cationic active site (CAS) where ACh is hydrolysed contains a catalytic triad of three amino acids, namely Ser 203, His 447 and Glu 334 (Colovic et al., 2013).
Comparative study of the nucleophilic attack step in the proteases catalytic activity: A theoretical study
Published in Molecular Physics, 2020
Sebastián A. Cuesta, José R. Mora, Cesar H. Zambrano, F. Javier Torres, Luis Rincón
When only one water molecule is considered in the calculation, a four-membered ring transition state is formed, where the carbon and the oxygen atoms of the carbonyl group and the hydrogen and oxygen atoms of the water molecule participate [Scheme 3 (i)]. An activation free energy of 47.3 kcal/mol was estimated for this step. In a second model [Scheme 3 (ii)], two water molecules were involved to form a six-membered transition state, for which an activation free energy of 44.9 kcal/mol was estimated, being slightly lower than the reaction with one solvent molecule. In the latter, the carbonyl group is protonated by extraction of a hydrogen atom of a first water molecule; at the same time, this deprotonated hydroxyl group activates a second water molecule, which finally attacks the carbon atom of the carbonyl group closing the ring in the transition state complex. The extra stabilisation of the transition state of the second system can be attributed to the lower structural tension of the six-membered ring in comparison to the four-membered one. Besides the differences between the transition states of the two reactions, it is clear that the spontaneous hydrolysis implies a high activation energy, suggesting the presence of a catalyst as requirement for the reaction to occur in nature. The spontaneous hydrolysis including more than two water molecules was considered in order to evaluate the presence of an oxyanion hole [76] around the carbonyl oxygen, which is expected to increase the electrophilicity of the carbon and consequently provide a lower activation free energy. In this sense, the activation free energy versus the number of water molecules was plotted in Figure 1, and as a result, it was observed that the activation energy decreases as the number of water molecules increases, being the minimum value associated to the system with four water molecules (ΔG‡ = 43.9 kcal/mol), while, the addition of a fifth water molecule results in an increase in the activation free energy, possibly due to steric effects. Based on this result, the model with four water molecules was defined as the reference to evaluate the catalytic action of the reactions simulated with the models depicted in Schemes 1 and 2. It is important to mention that the 3 extra water molecules added to the model simulate the presence of the oxyanion hole in the carbonyl group, which is further considered for the Cys- and Ser-protease because it stabilises the tetrahedral intermediate as well as the transition state making the carbon atom more susceptible for the nucleophilic attack [19,77,78].