Validation and Profiling of Physicochemical Properties Screening Methods for New Drug Candidate Optimization in Early Drug discovery

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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Druggable Transient Pockets in Protein Kinases

Molecules ◽

10.3390/molecules26030651 ◽

2021 ◽

Vol 26 (3) ◽

pp. 651

Author(s):

Koji Umezawa ◽

Isao Kii

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Protein Kinases ◽

Binding Sites ◽

Kinase Inhibitors ◽

Screening Methods ◽

Research Attention ◽

Folding Process ◽

Chemical Screening ◽

Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

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A chemoinformatic analysis of atoms, scaffolds and functional groups in natural products

Physical Sciences Reviews ◽

10.1515/psr-2019-0096 ◽

2021 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Joelle Ngo Hanna ◽

Boris D. Bekono ◽

Luc C. O. Owono ◽

Flavien A. A. Toze ◽

James A. Mbah ◽

...

Keyword(s):

Natural Products ◽

Drug Discovery ◽

Physicochemical Properties ◽

Functional Groups ◽

Atomic Composition ◽

Synthetic Compounds ◽

Chemical Libraries ◽

Synthetic Drugs ◽

Drugs Analysis ◽

Chemical Class

Abstract In the quest to know why natural products (NPs) have often been considered as privileged scaffolds for drug discovery purposes, many investigations into the differences between NPs and synthetic compounds have been carried out. Several attempts to answer this question have led to the investigation of the atomic composition, scaffolds and functional groups (FGs) of NPs, in comparison with synthetic drugs analysis. This chapter briefly describes an atomic enumeration method for chemical libraries that has been applied for the analysis of NP libraries, followed by a description of the main differences between NPs of marine and terrestrial origin in terms of their general physicochemical properties, most common scaffolds and “drug-likeness” properties. The last parts of the work describe an analysis of scaffolds and FGs common in NP libraries, focusing on huge NP databases, e.g. those in the Dictionary of Natural Products (DNP), NPs from cyanobacteria and the largest chemical class of NP – terpenoids.

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A Novel In Vitro Approach for Simultaneous Evaluation of CYP3A4 Inhibition and Kinetic Aqueous Solubility

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057114552796 ◽

2014 ◽

Vol 20 (2) ◽

pp. 254-264 ◽

Cited By ~ 3

Author(s):

José Pérez ◽

Caridad Díaz ◽

Francisco Asensio ◽

Alexandra Palafox ◽

Olga Genilloud ◽

...

Keyword(s):

Drug Discovery ◽

Physicochemical Properties ◽

Safety Concern ◽

Aqueous Solubility ◽

Cyp3a4 Inhibition ◽

Use Of Resources ◽

Simultaneous Evaluation ◽

New Chemical Entities ◽

Further Development

In the early stages of the drug discovery process, evaluation of the drug metabolism and physicochemical properties of new chemical entities is crucial to prioritize those candidates displaying a better profile for further development. In terms of metabolism, drug–drug interactions mediated through CYP450 inhibition are a significant safety concern, and therefore the effect of new candidate drugs on CYP450 activity should be screened early. In the initial stages of drug discovery, when physicochemical properties such as aqueous solubility have not been optimized yet, there might be a large number of candidate compounds showing artificially low CYP450 inhibition, and consequently potential drug–drug interaction toxicity might be overlooked. In this work, we present a novel in vitro approach for simultaneous evaluation of CYP3A4 inhibition potential and kinetic aqueous solubility (NIVA-CYPI-KS). This new methodology is based on fluorogenic CYP450 activities and turbidimetric measurements for compound solubility, and it provides a significant improvement in the use of resources and a better understanding of CYP450 inhibition data.

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High throughput P450 inhibition screens in early drug discovery

Drug Discovery Today ◽

10.1016/s1359-6446(05)03580-4 ◽

2005 ◽

Vol 10 (21) ◽

pp. 1443-1450 ◽

Cited By ~ 71

Author(s):

Gregor Zlokarnik ◽

Peter D.J. Grootenhuis ◽

John B. Watson

Keyword(s):

Drug Discovery ◽

High Throughput ◽

Early Drug

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