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Skin disorders in AIDS, immunodeficiency, and venereal disease
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
Indrashis Podder, Rashmi Sarkar
The first effective treatment for AIDS was zidovudine (AZT, azidothymidine), a reverse transcriptase inhibitor, given at 500–1500 mg per day in four to five divided doses. The drug slows down the progress of the HIV infection but comes nowhere near eliminating the viral infection. Unfortunately, it causes nausea, malaise, headache, and rash as well as many other side effects. Several other classes of antiretroviral drugs are now available. Other nucleoside analogue reverse transcriptase inhibitors include lamivudine, nevirapine, stavudine, delavirdine, and efavirenz. Other classes of drugs in use include protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Optimal regimens now usually consist of at least three drugs from two classes of antiretroviral agents. The newer antiviral drugs include enfuviritide (fusion inhibitor), maraviroc (blocks the entry of virus into cell by blocking the CD4 protein), and the integrase inhibitors (raltegravir, dolutegravir). Although promising, trials are going on to assess the efficacy of these drugs.
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Drugs that target enzymes are designed to inhibit their normal operation. This can be achieved in different ways. Competitive inhibitors mimic the molecular structure of normal substrate so that the drug can bind with a complimentary fit to the active site of the enzyme. This has the effect of blocking the active site, preventing entry of the normal substrate. The necessary reaction with the normal substrate cannot proceed, hence the biological process is subdued. The extent of this effect depends on the concentration of the drug, which in turn determines how many active sites are inhibited out of the plethora of catalytically available enzymes. Also important is the strength of binding of the drug to the active site, which effects the length of time that the drug remains in the active site; impacting the probability of normal biological catalysis happening. The nature of non-covalent interactions; being changeably broken and re-formed results in inhibition occurring dynamically. The weaker the intermolecular forces between the drug and the active site, the greater the proportion of unencumbered enzymes at any one time and the biological process will be inhibited to a lesser extent. The drug must be designed to optimise non-covalent interactions in order to be effective. Alternatively, the drug molecule could perhaps be designed to undergo reaction once in the active site to form a covalent bond to an amino acid residue. This is an irreversible form of inhibition and renders that enzyme molecule redundant.
Laboratory Detection of β-Lactam Resistance in Enterobacterales
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
The inhibitors used are: Boronic acid to inhibit class A KPC.EDTA to inhibit class B metallo-β-lactamase.Cloxacillin to inhibit class C AmpC β-lactamases. This test is used to differentiate between AmpC hyperproduction plus porin loss and carbapenemase-production.
Cloning, characterization, and inhibition of the novel β-carbonic anhydrase from parasitic blood fluke, Schistosoma mansoni
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Susanna Haapanen, Andrea Angeli, Martti Tolvanen, Reza Zolfaghari Emameh, Claudiu T. Supuran, Seppo Parkkila
Kinetic analysis of SmaBCA showed that the enzyme (with His-tag) is moderately active with kcat 1.38 × 105 s−1, Km 5.92 mM, and kcat/Km 2.33 × 107 M−1 s−1. Several sulphonamide and anion inhibitors46,62,63 were tested to evaluate their inhibitory properties against SmaBCA. The most efficient inhibitors showed submicromolar or nanomolar inhibitory effects on SmaBCA (Table 1 and Figure 5). The most efficient inhibitor with a KI of 43.8 nM was 4-(2-amino-pyrimidine-4-yl)-benzenesulfonamide (compound 19). Other effective inhibitors included several clinically used drugs. Benzolamide (BZA), brinzolamide (BRZ), topiramate (TPM), dorzolamide (DZA), saccharin (SAC), epacadostat (EPT), celecoxib (CLX), and famotidine (FAM) showed KIs in the range of 79.4–95.9 nM. The other tested compounds inhibited SmaBCA at micromolar or millimolar concentrations.
Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Prompted to “write a definition of mixed-type enzyme inhibition”, ChatGPT elaborated the following composition: Mixed-type enzyme inhibition is a form of enzyme inhibition where the inhibitor can bind to both the free enzyme and the enzyme-substrate complex, resulting in distinct effects on both the enzyme’s catalytic activity and its affinity for the substrate. In mixed-type inhibition, the inhibitor can interact with the enzyme at either the active or a separate allosteric site. […]Mixed-type enzyme inhibition is a complex regulatory mechanism that can have important implications in various biological processes and the development of therapeutic strategies targeting enzyme activity. Understanding the nature of mixed-type inhibition is crucial for studying enzyme kinetics, drug discovery, and the design of effective enzyme inhibitors. Because the algorithms of ChatGPT have been trained using a massive amount of text data, the response it provided can be considered as a representative description of mixed inhibition that aligns with the general understanding presented in articles, books and other scientific publications.
Unmasking allosteric-binding sites: novel targets for GPCR drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Verònica Casadó-Anguera, Vicent Casadó
The concept of allostery was proposed 60 years ago when the term ‘allosteric inhibition’ was used by Jacques Monod and Francois Jacob to describe a mechanism in which ‘the inhibitor is not a steric analogue of the substrate.’ Allostery consists in ‘an interaction between two topographically distinct sites on an enzyme mediated indirectly by a conformational change’ transmitted between the sites [4]. Shortly after, the mechanism underlying this conformational change was proposed to be the conformational selection. This mechanism predicts that the macromolecule exists in a thermal equilibrium between active and inactive states that can be stabilized by the binding of orthosteric or allosteric ligands to their respective (non-overlapping) binding sites [5]. This mechanism is commonly known as the concerted MWC model by Monod, Wyman, and Changeux [6]. According to this concerted model, different protomers (dimers, tetramers, …) can exist in two different states in equilibrium: a tense (T) state, which has low affinity for the ligand and is the most abundant in its absence, and a relaxed (R) state, which has high affinity for the ligand. All protomers must be in the same state at any time and ligand binding induces a concerted change of conformation of all protomers. Thus, according to this model, all protomers must be in the same conformation and symmetry has to be conserved. The oligomeric nature of the model is also able to explain the phenomenon of positive cooperativity in ligand binding, since the same ligand can bind to different protomers within the oligomer [5].