Designing Compound Libraries Targeting GPCRs

Solution NMR spectroscopy plays important roles in understanding protein structures, dynamics and protein-protein/ligand interactions. In a target-based drug discovery project, NMR can serve an important function in hit identification and lead optimization. Fluorine is a valuable probe for evaluating protein conformational changes and protein-ligand interactions. Accumulated studies demonstrate that 19F-NMR can play important roles in fragment- based drug discovery (FBDD) and probing protein-ligand interactions. This review summarizes the application of 19F-NMR in understanding protein-ligand interactions and drug discovery. Several examples are included to show the roles of 19F-NMR in confirming identified hits/leads in the drug discovery process. In addition to identifying hits from fluorinecontaining compound libraries, 19F-NMR will play an important role in drug discovery by providing a fast and robust way in novel hit identification. This technique can be used for ranking compounds with different binding affinities and is particularly useful for screening competitive compounds when a reference ligand is available.

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Microbial Genetic Screens for Monitoring Protein Misfolding Associated with Neurodegeneration: Tools for Identifying Disease-Relevant Genes and for Screening Synthetic and Natural Compound Libraries for the Discovery of Potential Therapeutics

Current Pharmaceutical Design ◽

10.2174/1381612824666180515143752 ◽

2018 ◽

Vol 24 (19) ◽

pp. 2055-2075 ◽

Cited By ~ 3

Author(s):

Kalliopi Kostelidou ◽

Ilias Matis ◽

Georgios Skretas

Keyword(s):

Protein Misfolding ◽

Socioeconomic Impact ◽

Genetic Screens ◽

Subsequent Formation ◽

The Past ◽

Compound Libraries ◽

Selection Systems ◽

Cellular Factors ◽

Effective Drugs ◽

Potential Therapeutics

Neurodegenerative Diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of highthroughput assays for the identification of cellular factors and processes that are important mediators of NDassociated proteotoxicities. In addition, such systems have facilitated the discovery of synthetic and natural compounds with the ability to rescue the misfolding and the associated pathogenic effects of aggregation-prone proteins associated with NDs. This review outlines such available systems in bacteria and yeast, whose usage will likely accelerate the pre-clinical discovery process for effective drugs against a variety of NDs with high socioeconomic impact.

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Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

2019 ◽

Vol 22 (8) ◽

pp. 509-520

Author(s):

Cauê B. Scarim ◽

Chung M. Chin

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Drug Candidates ◽

Lead Compounds ◽

New Drug ◽

Compound Libraries ◽

Screening Assays ◽

Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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