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Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
In order to maximise intermolecular binding interactions, the receptor protein changes conformation to accommodate the chemical message. This change of shape in the receptor induces a cellular response to the signal. It is therefore clear that to design a drug that targets a specific receptor, it must satisfy these non-covalent interactions and partake in complementary binding. Essentially, the drug must mimic the natural substrate in an analogous way to enzyme-substrate complex formation. Moreover, given that cellular receptors control biochemical processes within the cell, drugs can be designed that either enhance or suppress cellular activities. Drugs that are designed to closely mimic the natural substrate are agonists; they have the effect of increasing the concentration of chemical messages so that the receptor is more frequently activated and the biochemical process to which that receptor is linked will be enhanced. In some instances, a drug may be required to supress the activity of the cell: antagonists are designed to mimic the natural substrate closely enough to interact with the receptor, but are sufficiently different as to not trigger a response upon binding. This has the effect of decreasing the availability of receptors and suppress the activity.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
On the other hand, structure-based techniques helped in identifying TrypR as a potential target for some compounds active at the parasite level. This was the case for propyl/isopropyl quinoxaline-7- carboxylate 1,4-di-N-oxide-based compounds, active against T. cruzi, which were found to target TrypR by using docking simulations and enzymatic validation (Chaćon-Vargas et al. 2017). Arias et al. (2017) synthesized a set of nitrofuran derivatives, which demonstrated uncompetitive inhibition of TrypR in subsequent experiments. Docking studies indicated that the inhibitors may in fact be capable of binding to the enzyme-substrate complex, thus explaining the observed behavior. Similar observations were previously made for mesoionic 1,3,4-thiadiazolium-2-aminide (Rodrigues et al. 2012), which was also found to dock to TrypR in the presence of the substrate molecule. Finally, natural products or natural product-derived compounds, such as alkaloids or neolignan derivatives were proposed as inhibitors of TcTrypR on the basis of in silico screening, docking studies, and 2D-QSAR analysis (Argüelles et al. 2016, Hartmann et al. 2017).
Energy Demand of Muscle Machines
Published in Peter W. Hochachka, Muscles as Molecular and Metabolic Machines, 2019
In all studies of such mechanisms to this time, demonstration of a handoff requires proof that an enzyme-substrate complex serves as a competent substrate source for the target enzyme in the series. In the case of actomyosin ATPase, for example, one would need to know if the following reactions are favorable or possible:
The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Caitlin T. Di Paolo, Eleftherios P. Diamandis, Ioannis Prassas
Naturally derived compounds have also been identified as KLK inhibitors. Isocoumarins, which are a class of natural polyphenolic compounds, display inhibitor effects toward KLK5 and KLK7 [157]. Based on this finding, isomannide rigid scaffolds were used to devise isomannide-based peptidomimetic derivatives that improved inhibition constant (Ki) values to the submicromolar range for KLK5 [158,159]. More recently, another plant polyphenol called Brazilin was also identified with comparable Ki values to what was initially reported with the original isocoumarin compounds [160]. Fukugetin is a natural plant flavanone-flavone biflavonoid compound that also displays inhibitory activity toward the KLKs, but is unique in that it presents a mixed-type mechanism of inhibition that makes it useful for the development of an exosite-type inhibitor [161]. It is capable of binding both the free enzyme and the enzyme–substrate complex with two different affinity constants. Small natural plant-extracts called terterpenoids were also found to be selective toward only the trypsin-like KLKs [162]. 3-Acyltetramic acids are naturally occurring metabolites of terrestrial and marine organisms that exhibit a variety of biological properties such as antibacterial, antiviral, antifungal, and antihumoral activities [163]. They were found to be novel inhibitors of KLK5 and KLK7, with the nature and length of the acyl chain being crucial to the KLK5, KLK7, and trypsin inhibition activities [163].
Mechanistic and biological characterisation of novel N 5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Andrea Medeiros, Diego Benítez, Ricarda S. Korn, Vinicius C. Ferreira, Exequiel Barrera, Federico Carrión, Otto Pritsch, Sergio Pantano, Conrad Kunick, Camila I. de Oliveira, Oliver C. F. Orban, Marcelo A. Comini
As shown here, N5-substituted paullones are uncompetitive inhibitors of TryS with respect to ATP and GSH. Uncompetitive and mechanistic-based inhibitors are the most wanted, albeit rarely found, hits in screening campaigns since their design usually requires several rounds of hit optimisation. In an in vivo context, uncompetitive inhibition is not overcome, but enhanced, by substrate accumulation because the enzyme/ligand equilibrium is shifted to the formation of the enzyme–substrate complex for which the uncompetitive inhibitor has a higher affinity51. Probably, the higher potency of MOL2008 and 20 towards intracellular amastigotes than against extracellular promastigotes is in part exacerbated by the significant accumulation of GSH.
Kinetic and computational molecular docking simulation study of novel kojic acid derivatives as anti-tyrosinase and antioxidant agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Yan-Mei Chen, Chen Li, Wen-Jing Zhang, Yan Shi, Zi-Jie Wen, Qing-Xi Chen, Qin Wang
The oxidation of l-DOPA by tyrosinase was studied to ascertain the inhibitory behaviour of KADs. The relationship between the remaining enzyme activity and enzyme concentration in the presence of different concentrations of KADs was a family of straight lines that all pass through the origin (Figure 2). Increasing the inhibitor concentration resulted in lowering of the slope of the line, indicating that it is the reversible property of the inhibition by KADs. The outcomes showed that they could not deactivate permanently the enzyme to decrease the amount of active enzyme in the presence of KADs, merely depressed the enzyme activities. Lineweaver–Burk plot analysis (the plots of 1/v vs. 1/[l-DOPA]) gave a family of straight lines with different slopes that intercept in the second quadrant, indicating that two compounds can bind not only with free enzyme but also with the enzyme–substrate complex (Figure 3). The results demonstrated that KADs were classified as mixed type inhibitors. The inhibition constant (KI) was obtained from the plot of the slopes versus the concentrations of KADs. The enzyme–substrate complex (KIS) was also obtained from the plot of the vertical intercepts versus the concentrations of KADs, as shown in Table 1. In the case, the values of KIS are larger than KI.