Many Neglected Tropical Diseases (NTDs) have recently been subject of increased focus, particularly with relation to high-throughput screening (HTS) initiatives. These vital endeavours largely rely of two approaches, in vitro target-directed screening using biochemical assays or cell-based screening which takes no account of the target or targets being hit. Despite their successes both of these approaches have limitations; for example, the production of soluble protein and a lack of cellular context or the problems and expense of parasite cell culture. In addition, both can be challenging to miniaturize for ultra (u)HTS and expensive to utilize. Yeast-based systems offer a cost-effective approach to study and screen protein targets in a direct-directed manner within a eukaryotic cellular context. In this review, we examine the utility and limitations of yeast cell-based, target-directed screening. In particular we focus on the currently under-explored possibility of using such formats in uHTS screening campaigns for NTDs.
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http://dx.doi.org/10.1017/S0031182013000425 | DOI Listing |
Curr Comput Aided Drug Des
October 2021
Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, India.
Background: Development of resistance by the malaria parasite Plasmodium falciparum has created challenges in the eradication of this deadly infectious disease. Hence newer strategies are adopted to combat this disease and simultaneously, new lead/hit identification is going on worldwide to develop new chemotherapeutic agents against malaria.
Objective: In this study, 44 flavonoids found mainly in the fruit juice of Citrus species having traditional use in malaria-associated fever were selected for in silico multiple-target directed screening against three vital targets of the parasite namely dihydroorotate dehydrogenase (PfDHODH), dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation translocating ATPase (PfATP4) to find out new lead molecule(s).
Curr Alzheimer Res
September 2020
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Background: Accumulating evidence suggests that multi-target directed ligands have great potential for the treatment of complex diseases such as Alzheimer's Disease (AD).
Objective: To evaluate novel chimeric 8-hydroxyquinoline ligands with merged pharmacophores as potential multifunctional ligands for AD.
Methods: Nitroxoline, PBT2 and compounds 2-4 were evaluated in-vitro for their inhibitory potencies on cathepsin B, cholinesterases, and monoamine oxidases.
Eur J Med Chem
April 2019
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address:
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition).
View Article and Find Full Text PDFExpert Opin Biol Ther
August 2018
a Sandoz Biopharmaceuticals/Hexal AG , Holzkirchen , Germany.
Background: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.
View Article and Find Full Text PDFMolecules
March 2016
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy.
The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B.
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