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Biocatalysts: The Different Classes and Applications for Synthesis of APIs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
These hydrolyzing enzymes catalyze the cleavage of a covalent bond using water. Hydrolases comprise lipases, esterases, proteases, nitrilases, epoxidases, and hydantoinases. They are attractive candidates for application in organic synthesis because they need no costly cofactors that must be recycled as prerequisite for an economic production. Many of these enzymes contain a nucleophilic serine as part of the catalytic triad that contains in addition an aspartate or glutamate as acidic and a histidine as basic residue; hydrolysis proceeds via the formation of an acyl-enzyme intermediate through a nucleophilic attack of the hydroxyl group of Ser on the carbonyl carbon (formation of an ester bond) which is followed by a nucleophilic attack of the water oxygen on the carbonyl carbon of the acyl-enzyme intermediate leading to its hydrolysis and regeneration of the enzyme.
Chikungunya Virus Infection
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
D. Velmurugan, K. Manish, D. Gayathri
Cheung et al. (2011) first reported the crystal structure of CHIKV nsP2 protease, constituted mainly by 14 helices (H1-H14) and 3 sheets formed by 12 strands. The catalytic triad is formed by the active site amino acids Cys1013 and His1083. Cys1013 is held at the N-terminus by the H1 helix and His1083 is held by the linker region of first two strands. Before this, some studies on the structure function relationship of CHIKV-nsP2 protease were carried out taking into account the available structural information of the alphavirus nsP2 protease from Venezuelan equine encephalitis virus (VEEV) or the cysteine protease from papain.
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).
A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Tereza Cristina Santos Evangelista, Óscar López, Adrián Puerta, Miguel X. Fernandes, Sabrina Baptista Ferreira, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
X-ray analysis has demonstrated that the overall structure of AChE and BuChE is very similar and that both enzymes host a catalytic triad consisting of histidine, glutamate, and serine almost on the bottom of a ca. 20 Å deep active gorge.18,19 Both enzymes contain a tryptophan residue in the catalytic anionic binding site (CAS) nearby the catalytic triad, which establishes π–cation interactions with the cationic ACh substrate and thereby place its ester functional group in a favourable position for hydrolysis in the catalytic triad.20 At the mouth of the active site gorge of both enzymes there is an initial substrate binding site, the peripheral anionic binding site (PAS), which is structurally different between AChE and BuChE as the PAS of AChE is more rich in aromatic residues.21
Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Hyun Myung Lee, Rudolf Andrys, Jakub Jonczyk, Kyuneun Kim, Avinash G. Vishakantegowda, David Malinak, Adam Skarka, Monika Schmidt, Michaela Vaskova, Kamil Latka, Marek Bajda, Young-Sik Jung, Barbara Malawska, Kamil Musilek
The three-dimensional ligand structures were built with the Corina online tool (Molecular Networks GmbH, Erlangen, Germany & Altamira). Oximes were prepared in the anionic form. Before docking, atom types and protonation states of ligand structures were checked and Gasteiger-Marsili charges were assigned using Sybyl-X 1.1 (Tripos, St. Louis, MO). All proteins used in the docking studies were prepared with ProteinPrepare web service (pH 7.4, without water molecules, including heteroatoms in pKa calculation)21. Docking studies were divided into three parts. In the first part, the inhibition of AChE and BChE by oximes was performed on mouse apo enzymes, i.e. AChE (PDB code: 1J06) and human BChE (PDB code: 1P0I) with the Gold Suite 5.3 (The Cambridge Crystallographic Data Centre, Cambridge, UK). The binding site was defined with all amino acid residues within 15 Å from the serine of the catalytic triad. A standard set of genetic algorithm parameters with a population size of 100 and a number of operations of 100,000 was applied. As a result, 10 ligand conformations were obtained and sorted according to the values of scoring function – GoldScore.
Modulators of calpain activity: inhibitors and activators as potential drugs
Published in Expert Opinion on Drug Discovery, 2020
Levente Endre Dókus, Mo’ath Yousef, Zoltán Bánóczi
The CysPc domain of a calpain is composed of a protease core 1 (PC1) and PC2 domains. Amino acids that form the catalytic triad were in distinct domains; the Cys is in the PC1 while the His and Asn are in the PC2 domain. Calpain 6 is the only member that does not have a catalytic triad as there is Lys instead of Cys. In the absence of Ca2+ ions, these two domains are far from each other and, thus, the catalytic triad is not assembled [8]. Both domains can bind with Ca2+ ions and that results in structural changes, with the opening of the active site cleft and the assembly of the catalytic triad [9] (the relationship between its structure and activity is well summarized in Ref [10]). Although the whole 3D structure of only calpain 2 is known (Figure 2(a)) [9,11], its use for the 3D modeling of other calpains is an accepted strategy [12,13].