Plantago ovata (Isabgol) and Rauvolfia serpentina (Indian Snakeroot)
Azamal Husen in Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Hypercholesterolemia has been associated with diabetes and various cardiovascular diseases. The increased amount of cholesterol synthesis is caused by high activity of HMGCR (3-hydroxy-3-methyl-glutaryl CoA reductase) enzyme. Thus, the enzyme is a prominent drug target for inhibition. A study was conducted on the effect of alkaloids from roots of R. serpentina toward HMGCR activity using in silico investigations. This study concluded that, of the 12 alkaloids tested, ajmalicine, reserpine, indobinine, yohimbine, and indobine are predicted as the potent inhibitors of HMGCR and suppress cholesterol synthesis. Thus the five alkaloids can serve as potential lead compounds for developing new drugs against hyperlipidemia (Azmi et al., 2021). Another study on methanolic extract of R. serpentina reported its hypotensive and hypolipidemic effects (Shah et al., 2020).
Finding a Target
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
Enzyme inhibitors have been used widely in medicine. To combat infections from microorganisms; shutting down enzymes that are crucial to the function of the bacterial cell will kill the cell or prevent proliferation. It is possible to selectively target bacterial enzymes without effecting our own due to the large biochemical differences between bacteria and ourselves. For example, some of the first antibiotics were the sulphonamides. These acted as competitive inhibitors and medicinal chemists synthesised a library of these compounds to optimise binding interactions to improve efficacy. These drugs were the antibiotics of choice prior to been superseded by penicillin, which also function as competitive enzyme inhibitors, except on a different target. In the fight against viruses, successful antiviral drugs have been developed that work against viral enzymes. Acyclovir for the treatment of herpes and saquinavir for HIV are both enzyme inhibitors. Besides battling against foreign invaders, enzyme inhibitors can be utilized to work against the body’s own enzymes and thus regulate and offer control over the cells biological operations. Anticholinesterases are an example where inhibitors of enzymes were developed for control of problems with the nervous system.
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Anton C. de Groot in Monographs in Contact Allergy, 2021
Ketorolac tromethamine is a pyrrolizine carboxylic acid derivative and nonsteroidal anti-inflammatory drug (NSAID) with antipyretic, analgesic and anti-inflammatory properties. It is a non-selective inhibitor of the cyclooxygenases (COX), inhibiting both COX-1 and COX-2 enzymes. This agent exerts its anti-inflammatory effect by preventing conversion of arachidonic acid to prostaglandins at inflammation sites mediated through inhibition of COX-2. Ketorolac tromethamine is indicated for short term management of acute pain that requires the caliber of pain management offered by opioids, e.g. for the management of post-operative pain, spinal and soft tissue pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, menstrual disorders and headaches (1).
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
Alessandro Pesaresi
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].
An update of targeted therapeutic options for primary Sjögren syndrome: current status and future development
Published in Expert Opinion on Pharmacotherapy, 2021
Soledad Retamozo, Antoni Sisó-Almirall, Alejandra Flores-Chávez, Manuel Ramos-Casals, Pilar Brito-Zerón
Kinases are a group of enzymes that transfer a phosphate group to a protein, playing a key role in maintaining cellular function by turning protein function on, while other enzymes (phosphatases) reverse this action [77]. Approximately 538 known kinases are encoded in the human genome, which are subdivided into seven families of typical and seven families of atypical protein kinases. One of the more recent therapeutic approaches to control autoimmune and inflammatory responses has been to target the activity of kinases [78]. Inhibition of kinases may be achieved by means of small molecules designed to interfere with the enzyme regardless of its cellular location, or by monoclonal antibodies (mAbs) targeting kinase receptors located at the cell surface. Small-molecule inhibitors are molecules ≤500 Da in size (the names of the molecules use the stem ‘-ib’ at the end) [79], while the names of mAbs use the general stem ‘-mab,’ with specific sub-stems according to the source (‘-ximab’ for chimeric mAbs, ‘zumab’ for humanized mAbs, and ‘-mumab’ for fully human mAbs) [80].
Related Knowledge Centers
- Active Site
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- Enzyme
- Enzyme Assay
- Enzyme Catalysis
- Molecule
- Protein
- Substrate
- Product
- Rate-Determining Step