scholarly journals Probing Multi-Target Action of Phlorotannins as New Monoamine Oxidase Inhibitors and Dopaminergic Receptor Modulators with the Potential for Treatment of Neuronal Disorders

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 377 ◽  
Author(s):  
Su Hui Seong ◽  
Pradeep Paudel ◽  
Jeong-Wook Choi ◽  
Dong Hyun Ahn ◽  
Taek-Jeong Nam ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Active Sites ◽  
Binding Pocket ◽  
Functional Assay ◽  
Protein Targets ◽  
Multiple Protein ◽  
Target Action ◽  
Binding Pockets ◽  
Single Compound ◽  
Neuronal Disorders

Modulation of multiple protein targets with a single compound is essential for the effective treatment of central nervous system disorders. In our previous G protein-coupled receptor (GPCR) cell-based study, a selective human monoamine oxidase (hMAO)-A inhibitor, eckol, stimulated activity of dopamine D3 and D4 receptors. This result led to our interest in marine phlorotannin-mediated modulation of hMAO enzymes and related GPCRs in neuronal disorders. Here, we evaluate the multi-target effects of phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol by screening their modulatory activity against hMAO-A and -B and various neuronal GPCRs. Among the tested phlorotannins, PFF-A showed the strongest inhibitory activity against both hMAO isoforms, with higher selectivity toward hMAO-B than hMAO-A. Enzyme kinetics and docking data revealed that PFF-A noncompetitively acts on hMAOs into the alternative binding pocket of enzymes with allosteric functions. In a functional assay for GPCR screening, dieckol and PFF-A exhibited a multi-target combination of D3R/D4R agonism and D1/5HT1A/NK1 antagonism. In particular, they effectively stimulated D3R and D4R, compared to other GPCRs. Docking analysis confirmed that dieckol and PFF-A successfully docked into the conserved active sites of D3R and D4R and interacted with aspartyl and serine residues in the orthosteric binding pockets of the respective receptors. Based on our experimental and computational data, we established the structure-activity relationship between tested phlorotannins and target proteins, including hMAOs and GPCRs. Our current findings suggest that hMAO inhibitors dieckol and PFF-A, major phlorotannins of edible brown algae with multi-action on GPCRs, are potential agents for treatment of psychological disorders and Parkinson’s disease.

Computational Strategy Revealing the Structural Determinant of Ligand Selectivity towards Highly Similar Protein Targets

2019 ◽  
Vol 21 (1) ◽  
pp. 76-88
Author(s):  
Hanxun Wang ◽  
Yinli Gao ◽  
Jian Wang ◽  
Maosheng Cheng
Keyword(s):  
Side Effects ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Protein Targets ◽  
Ligand Selectivity ◽  
Drug Candidates ◽  
Multiple Strategies ◽  
Similar Protein ◽  
Single Target ◽  
Binding Pockets

Background: Poor selectivity of drug candidates may lead to toxicity and side effects accounting for as high as 60% failure rate, thus, the selectivity is consistently significant and challenging for drug discovery. Objective: To find highly specific small molecules towards very similar protein targets, multiple strategies are always employed, including (1) To make use of the diverse shape of binding pocket to avoid steric bump; (2) To increase binding affinities for favorite residues; (3) To achieve selectivity through allosteric regulation of target; (4) To stabalize the inactive conformation of protein target and (5) To occupy dual binding pockets of single target. Conclusion: In this review, we summarize computational strategies along with examples of their successful applications in designing selective ligands, with the aim to provide insights into everdiversifying drug development practice and inspire medicinal chemists to utilize computational strategies to avoid potential side effects due to low selectivity of ligands.

Fluorescent nanoparticle sensors with tailor-made recognition units and proximate fluorescent reporter groups

2018 ◽  
Vol 42 (12) ◽  
pp. 9377-9380 ◽  
Author(s):  
Xiaoyu Xing ◽  
Yan Zhao
Keyword(s):  
Molecular Imprinting ◽  
Binding Pocket ◽  
Fluorescent Sensors ◽  
Covalent Modification ◽  
Fluorescent Reporter ◽  
Binding Pockets ◽  
Fluorescent Nanoparticle

Molecular imprinting in micelles followed by covalent modification of the binding pocket yielded fluorescent sensors with precisely constructed binding pockets.

scholarly journals Exploring Multi‐Subsite Binding Pockets in Proteins: DEEP‐STD NMR Fingerprinting and Molecular Dynamics Unveil a Cryptic Subsite at the GM1 Binding Pocket of Cholera Toxin B

2020 ◽  
Vol 26 (44) ◽  
pp. 10024-10034
Author(s):  
Serena Monaco ◽  
Samuel Walpole ◽  
Hassan Doukani ◽  
Ridvan Nepravishta ◽  
Macarena Martínez‐Bailén ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cholera Toxin ◽  
Binding Pocket ◽  
Toxin B ◽  
Cholera Toxin B ◽  
Binding Pockets ◽  
Std Nmr

scholarly journals A Comprehensive Mapping of the Druggable Cavities within the SARS-CoV-2 Therapeutically Relevant Proteins by Combining Pocket and Docking Searches as Implemented in Pockets 2.0

2020 ◽  
Vol 21 (14) ◽  
pp. 5152 ◽  
Author(s):  
Silvia Gervasoni ◽  
Giulio Vistoli ◽  
Carmine Talarico ◽  
Candida Manelfi ◽  
Andrea R. Beccari ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Repurposing ◽  
Protein Targets ◽  
In Silico Studies ◽  
Allosteric Sites ◽  
Binding Pockets ◽  
Novel Strategy ◽  
Better Than ◽  
Comprehensive Mapping

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.

Mutational analysis of the flavinylation and binding motifs in two protein targets of the flavin transferase ApbE

2019 ◽  
Vol 366 (22) ◽  
Author(s):  
Yulia V Bertsova ◽  
Marina V Serebryakova ◽  
Victor A Anashkin ◽  
Alexander A Baykov ◽  
Alexander V Bogachev
Keyword(s):  
Mutational Analysis ◽  
Vibrio Harveyi ◽  
Binding Pocket ◽  
Serine Residue ◽  
Specific Enzyme ◽  
Protein Targets ◽  
Binding Motifs ◽  
Nadh:Quinone Oxidoreductase ◽  
Escherichia Coli Cells

ABSTRACT Many flavoproteins belonging to three domain types contain an FMN residue linked through a phosphoester bond to a threonine or serine residue found in a conserved seven-residue motif. The flavinylation reaction is catalyzed by a specific enzyme, ApbE, which uses FAD as a substrate. To determine the structural requirements of the flavinylation reaction, we examined the effects of single substitutions in the flavinylation motif of Klebsiella pneumoniae cytoplasmic fumarate reductase on its modification by its own ApbE in recombinant Escherichia coli cells. The replacement of the flavin acceptor threonine with alanine completely abolished the modification reaction, whereas the replacements of conserved aspartate and serine had only minor effects. Effects of other substitutions, including replacing the acceptor threonine with serine, (a 10–55% decrease in the flavinylation degree) pinpointed important glycine and alanine residues and suggested an excessive capacity of the ApbE-based flavinylation system in vivo. Consistent with this deduction, drastic replacements of conserved leucine and threonine residues in the binding pocket that accommodates FMN residue still allowed appreciable flavinylation of the NqrC subunit of Vibrio harveyi Na+-translocating NADH:quinone oxidoreductase, despite a profound weakening of the isoalloxazine ring binding and an increase in its exposure to solvent.

scholarly journals On the possible origin of protein homochirality, structure, and biochemical function

2019 ◽  
Vol 116 (52) ◽  
pp. 26571-26579 ◽  
Author(s):  
Jeffrey Skolnick ◽  
Hongyi Zhou ◽  
Mu Gao
Keyword(s):  
Amino Acids ◽  
Active Site ◽  
Ribosomal Proteins ◽  
Active Sites ◽  
Cell Formation ◽  
Binding Pocket ◽  
Nucleotide Biosynthesis ◽  
Native Proteins ◽  
Structural And Functional Properties ◽  
Biochemical Function

Living systems have chiral molecules, e.g., native proteins that almost entirely contain L-amino acids. How protein homochirality emerged from a background of equal numbers of L and D amino acids is among many questions about life’s origin. The origin of homochirality and its implications are explored in computer simulations examining the stability and structural and functional properties of an artificial library of compact proteins containing 1:1 (termed demi-chiral), 3:1, and 1:3 ratios of D:L and purely L or D amino acids generated without functional selection. Demi-chiral proteins have shorter secondary structures and fewer internal hydrogen bonds and are less stable than homochiral proteins. Selection for hydrogen bonding yields a preponderance of L or D amino acids. Demi-chiral proteins have native global folds, including similarity to early ribosomal proteins, similar small molecule ligand binding pocket geometries, and many constellations of L-chiral amino acids with a 1.0-Å RMSD to native enzyme active sites. For a representative subset containing 550 active site geometries matching 457 (2) 4-digit (3-digit) enzyme classification (E.C.) numbers, native active site amino acids were generated at random for 472 of 550 cases. This increases to 548 of 550 cases when similar residues are allowed. The most frequently generated sequences correspond to ancient enzymatic functions, e.g., glycolysis, replication, and nucleotide biosynthesis. Surprisingly, even without selection, demi-chiral proteins possess the requisite marginal biochemical function and structure of modern proteins, but were thermodynamically less stable. If demi-chiral proteins were present, they could engage in early metabolism, which created the feedback loop for transcription and cell formation.

Rapid synthesis of flavone-based monoamine oxidase (MAO) inhibitors targeting two active sites using click chemistry

2016 ◽  
Vol 89 (1) ◽  
pp. 141-151 ◽  
Author(s):  
Wei Zhen Jia ◽  
Feng Cheng ◽  
Yin Jun Zhang ◽  
Jin Yan Ge ◽  
Shao Q. Yao ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Click Chemistry ◽  
Active Sites ◽  
Mao Inhibitors ◽  
Rapid Synthesis
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