Natural allosteric modulators and their biological targets: molecular signatures and mechanisms

Bruder, Marjorie; Polo, Gina; Trivella, Daniela Barretto Barbosa

doi:10.1039/c9np00064j

Cited by 21 publications

(22 citation statements)

References 215 publications

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“…[32][33][34][35] In addition, the lack of structural mechanistic knowledge hinders compound modification and lead optimization. 28,33,[36][37][38] Taken together, these factors invoke a demand for more powerful methods that provide in-depth insight into allosterism and can guide allosteric drug design.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, current allosteric drugs were largely discovered by serendipity or retrieved from exhaustive large‐scale compound‐library screening, both of which are tedious processes, expensive from both experimental‐effort and resource perspectives 32–35 . In addition, the lack of structural mechanistic knowledge hinders compound modification and lead optimization 28,33,36–38 . Taken together, these factors invoke a demand for more powerful methods that provide in‐depth insight into allosterism and can guide allosteric drug design.…”

Section: Introductionmentioning

confidence: 99%

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Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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Allostery is a universal, biological phenomenon in which orthosteric sites are finetuned by topologically distal allosteric sites triggered by perturbations, such as ligand binding, residue mutations, or post-translational modifications. Allosteric regulation is implicated in a variety of physiological and pathological conditions and is thus emerging as a novel avenue for drug discovery. Allosteric drugs have traditionally been discovered by serendipity through large-scale experimental screening. Recently, we have witnessed significant progress in biophysics, particularly in structural bioinformatics, which has facilitated the in-depth characterization of allosteric effects and the accurate detection of allosteric residues and exosites. These advances improve our understanding of allosterism and promote allosteric drug discovery, thereby revolutionizing the shift from the traditional serendipitous route used to discover allosteric drugs to the updated path centered on rational structure-based design. In this review, recent advances in computational methods applied to allosteric drug discovery are summarized. We comprehensively review these achievements along various levels of allosteric events, from the construction of allosteric databases to the identification and analysis of allosteric residues, signals, sites, and modulators. We expect to increase the awareness of the discovery of allosteric drugs using structure-based computational methods.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

View full text Add to dashboard Cite

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“…nicotinic ion channels) are well-established drugs; however, it is a relatively new field regarding GPCRs. It is also worth emphasizing that among the 20 allosteric drugs approved by the FDA, only a few have been developed applying an allosteric approach (i.e., GPCR targeting drugs mentioned above and trametinib and cobimetinib targeting kinases) [21]. In contrast, the allosteric mode of action of benzodiazepines on GABA A receptors was demonstrated decades after their development in the 1950s [21].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

2022

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Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays a hot topic in medicinal chemistry. Allosteric modulators, i.e., compounds which bind in a receptor site topologically distinct from orthosteric sites, exhibit a number of advantages. They are more selective, safer and display a ceiling effect which prevents overdosing. Allosteric modulators of dopamine D2 receptor are potential drugs against a number of psychiatric and neurological diseases, such as schizophrenia and Parkinson’s disease. In this review, an insightful summary of current research on D2 receptor modulators is presented, ranging from their pharmacology and structural aspects of ligand-receptor interactions to their synthesis.

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“…Amalgamations of drugs endowed with different medicinal activities have been dispensed to patients for decades. It is known that an adapted adjustment of different targets may offer an improved medicinal aspect and an advantageous side effect in contrast with the effect of a ligand that has a unique mode of action [ 1 ]. In comparison with drug combinations, there are several betterments emanating from drugs active on several receptors, including the more foreseeable pharmacokinetics and pharmacodynamics properties resulting of the treatment of a unique medicinal drug in addition to ameliorated patient acquiescence.…”

Section: Introductionmentioning

confidence: 99%

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation

et al. 2021

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Background: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance of microbes to existing drugs creates the need for the development of new effective antimicrobial agents. In an attempt to improve the antibacterial activity of previously synthesized compounds modifications to their structures were performed. Methods: Nineteen thiazolidinone derivatives with 6-Cl, 4-OMe, 6-CN, 6-adamantan, 4-Me, 6-adamantan substituents at benzothiazole ring were synthesized and evaluated against panel of four bacterial strains S. aureus, L. monocytogenes, E. coli and S. typhimirium and three resistant strains MRSA, E. coli and P. aeruginosa in order to improve activity of previously evaluated 6-OCF3-benzothiazole-based thiazolidinones. The evaluation of minimum inhibitory and minimum bactericidal concentration was determined by microdilution method. As reference compounds ampicillin and streptomycin were used. Results: All compounds showed antibacterial activity with MIC in range of 0.12–0.75 mg/mL and MBC at 0.25–>1.00 mg/mL The most active compound among all tested appeared to be compound 18, with MIC at 0.10 mg/mL and MBC at 0.12 mg/mL against P. aeruginosa. as well as against resistant strain P. aeruginosa with MIC at 0.06 mg/mL and MBC at 0.12 mg/mL almost equipotent with streptomycin and better than ampicillin. Docking studies predicted that the inhibition of LD-carboxypeptidase is probably the possible mechanism of antibacterial activity of tested compounds. Conclusion: The best improvement of antibacterial activity after modifications was achieved by replacement of 6-OCF3 substituent in benzothiazole moiety by 6-Cl against S. aureus, MRSA and resistant strain of E. coli by 2.5 folds, while against L. monocytogenes and S. typhimirium from 4 to 5 folds.

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Natural allosteric modulators and their biological targets: molecular signatures and mechanisms

Abstract: Natural allosteric modulators reported over the last decade are reviewed on a chemical and mechanistic basis, emphasising the importance of natural products as probes for future allosteric drugs.

Cited by 21 publications

References 215 publications

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation

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