China
Africa
Explore chapters and articles related to this topic
Phytonanotechnology
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Tafadzwa J. Chiome, Asha Srinivasan
Drug discovery is a process by which potential and novel plant-based compounds are discovered after screening for therapeutic efficacy. The process through which a lead compound can be transformed into a commercial product can take up to 10–15 years for its development. Pharmaceutical companies have several approaches toward new drug discovery and development. However, two approaches are favored: phenotypic drug discovery and target-based drug discovery. In both these methods, the new drug discovery process involves rational drug design after initial target identification. In target-based drug discovery, the target is generally a gene or a protein that is linked with a disease. The success of new drug design is dependent on a target identification of a particular drug. The ability of a drug to bind to its target is assessed, with a thorough understanding of structural and thermodynamic basis on protein-ligand interactions, as it is this interaction that will initiate a cascade of biological events in response to the drug (Baker et al., 1995).
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
High throughput screening using natural products as a lead is a common strategy for drug discovery and is very useful for PTPs because relative simple in vitro assays can be performed. But, rationally developing PTP inhibitors by structure-based information is increasing and the strategies used for this research are being optimized (104). Although all Cys-based PTPs share a catalytic domain with a low pKa, the surface topology surrounding this catalytic pocket has numerous unique features, for instance, the differences in charge distribution, which allow for inhibitor specificity and can be utilized for rational structure-based design of highly selective compounds (107).
Key Concepts in Assay Development, Screening and the Properties of Lead and Candidate Compounds
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
The ranking of the confidence in target validation can conveniently be classified using a score ranging from 1 (least confidence) through to 4 (most confidence), as shown in Figure 2. The ranking is also consistent with the progression of most drug discovery projects as the initial steps are biology focused and upon understanding target mechanism of action. The attention then shifts to a chemistry focus where compounds are designed, synthesised and evaluated in vitro and in vivo to confirm that they are able to modulate the activity of the biological target in a manner that could be therapeutically relevant (Bhullar et al. 2018, García-Aranda and Redondo 2017, Mohs and Greig 2017). The best assessment for validating a particular target from a drug discovery perspective would come from the existence of a therapeutic agent that has successfully been shown to yield clinical benefit. However, this scenario is not optimal when searching for novel first-in-class drugs as the existence of a competitor molecule would impact the revenue generating potential of an additional drug.
Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Faten Farouk, Ayman Abo Elmaaty, Ahmed Elkamhawy, Haytham O. Tawfik, Radwan Alnajjar, Mohammed A. S. Abourehab, Mohamed A. Saleh, Wagdy M. Eldehna, Ahmed A. Al‐Karmalawy
Immense research is taking place on the development of novel TOP-2 inhibitors. The journey for the development of a new drug candidate from drug discovery to FDA approval is an economically exhausting process with a low degree of success and uncertainty19,20. Repurposing drug candidates that are already approved by the FDA can surpass such time and cost resource consumption; meanwhile, reducing the incidence of developing a new agent with significant side effects that may impact the health of patients21,22. Repurposing FDA-approved drugs may also reduce the chemical consumption that is exerted in the development process which is a global quest for climate change. In addition, the utilisation of some in-silico approaches, such as molecular docking and molecular dynamics have a crucial role in the drug repurposing process by affording deep insights about the affinity of the repurposed compounds to the new specified targets and putting eyes on the possible capability of these compounds to be dedicated for new therapeutic uses along with their primary therapeutic uses23–25.
Parasite and host kinases as targets for antimalarials
Published in Expert Opinion on Therapeutic Targets, 2023
Han Wee Ong, Jack Adderley, Andrew B. Tobin, David H. Drewry, Christian Doerig
Target identification is crucial toward realizing the benefits of target-based drug discovery. Two major target identification techniques have been used to identify antiplasmodial kinase targets. In vitro resistance generation with follow-up whole-genome sequencing is one such technique used frequently for identification of targets of kinase inhibitors. This has been successfully implemented for the imidazopyrazine KDU691 (PfPI4Kβ) [13], the 2-aminopyridine MMV390048 (PfPI4Kβ) [14], the 2-aminopyrazine UCT943 (PfPI4Kβ) [15], and 7-azaindole TCMDC-135051 (PfCLK3) [16]. Chemoproteomics is the other broad class of commonly-utilized target-identification technique, as reviewed in [17]. The main benefits of chemoproteomics are that it offers evidence of direct target engagement, and it may be utilized even when the target is refractory to resistance generation. One contributing factor to the popularity of chemoproteomics in kinase target identification is due to the availability of the established Kinobead technology, which uses a selection of promiscuous kinase inhibitors immobilized onto Sepharose beads to pull down kinases from cell lysates [18]. While originally designed for human kinase pulldowns, Kinobeads has been repurposed for pulldowns of kinases from Plasmodium lysate [14,18–22]. This technique has been implemented successfully in the identification of the kinase targets of the 2-aminopyridine MMV390048 (PfPI4Kβ) [14], pyridine-imidazole MMV030084 (PfPKG) [22], aminopyrimidine-thiazole compounds (PfPKG) [20,21], and purfalcamine (PfCDPK1) [23].
Methyl-hydroxylation and subsequent oxidation to produce carboxylic acid is the major metabolic pathway of tolbutamide in chimeric TK-NOG mice transplanted with human hepatocytes
Published in Xenobiotica, 2021
Shotaro Uehara, Nao Yoneda, Yuichiro Higuchi, Hiroshi Yamazaki, Hiroshi Suemizu
Preclinical drug metabolism studies play an important role in lead molecule identification and optimisation in the drug discovery process. Characterisation of the metabolic pathways of novel drug candidates is integral to drug discovery and development, specifically to optimise pharmacokinetic properties and eliminate or minimise potential safety liabilities associated with the formation of chemically toxic/reactive metabolites (Baillie 2008). Experimental animal models are widely used during preclinical development. Significant interspecies differences in drug metabolism are largely attributable to differences in the isoform composition, regulation, expression, and substrate specificity of drug-metabolising enzymes, such as cytochrome P450 enzymes (Martignoni et al.2006) and aldehyde oxidase (AOX) (Garattini et al.2009), which play important roles in oxidative drug reactions. Therefore, assessing drug metabolism and its toxicological and pharmacokinetic effects using appropriate experimental animals may improve the success rate of preclinical drug development.