scholarly journals Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4206 ◽  
Author(s):  
Qi Li ◽  
Hongyu Yang ◽  
Jun Mo ◽  
Yao Chen ◽  
Yue Wu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Inhibitory Activity ◽  
Skin Pigmentation ◽  
Competitive Inhibitor ◽  
Tyrosinase Inhibitor ◽  
Starting Point ◽  
Good Starting Point ◽  
Tyrosinase Inhibitors ◽  
Dopa Formation ◽  
Potent Inhibitory Activity

Targeting tyrosinase is considered to be an effective way to control the production of melanin. Tyrosinase inhibitor is anticipated to provide new therapy to prevent skin pigmentation, melanoma and neurodegenerative diseases. Herein, we report our results in identifying new tyrosinase inhibitors. The shape-based virtual screening was performed to discover new tyrosinase inhibitors. Thirteen potential hits derived from virtual screening were tested by biological determinations. Compound 5186-0429 exhibited the most potent inhibitory activity. It dose-dependently inhibited the activity of tyrosinase, with the IC50 values 6.2 ± 2.0 µM and 10.3 ± 5.4 µM on tyrosine and L-Dopa formation, respectively. The kinetic study of 5186-0429 demonstrated that this compound acted as a competitive inhibitor. We believe the discoveries here could serve as a good starting point for further design of potent tyrosinase inhibitor.

scholarly journals Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

2021 ◽  
Vol 14 (3) ◽  
pp. 203 ◽  
Author(s):  
Shurong Hou ◽  
Juan Diez ◽  
Chao Wang ◽  
Christoph Becker-Pauly ◽  
Gregg B. Fields ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
De Novo ◽  
Selective Inhibitors ◽  
Preclinical Development ◽  
Starting Point ◽  
Good Starting Point ◽  
Parallel Screening ◽  
Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.

Phlorotannins Derived From the Brown Alga Colpomenia bullosa as Tyrosinase Inhibitors

2021 ◽  
Vol 16 (7) ◽  
pp. 1934578X2110213
Author(s):  
Hideyuki Kurihara ◽  
Kazuki Kujira
Keyword(s):  
Inhibitory Activity ◽  
Brown Alga ◽  
Molecular Structures ◽  
Free Form ◽  
Biosynthesis Pathway ◽  
Tyrosinase Inhibitor ◽  
Melanin Biosynthesis ◽  
Tyrosinase Inhibitory Activity ◽  
Tyrosinase Inhibitors ◽  
Potential Use

Tyrosinase catalyzes hydroxylation of L-tyrosine and dehydrogenation of L-DOPA in the melanin biosynthesis pathway. Tyrosinase inhibitors have potential use as cosmetic whitening agents and for preventing seafood deterioration. In this report, tyrosinase inhibitors extracted from brown alga Colpomenia bullosa (Scytosiphonaceae, Scytosiphonales) were investigated. Inhibitory principles were isolated from the extract and identified as phlorotannins, phloroglucinol (1), diphlorethol (2), triphlorethol C (3), which have not been isolated in a free form previously, and fucophlorethol C (4). Compounds 3 and 4 have not been reported previously as tyrosinase inhibitors. Triphlorethol C (3) was the most potent tyrosinase inhibitor among the phlorotannins isolated, whereas isomeric fucophlorethol C (4) displayed the weakest inhibitory activity. The results suggest that molecular structures of phlorotannins strongly affect their tyrosinase inhibitory activity.

The effect of chlorophorin and its derivative on melanin biosynthesis

Holzforschung ◽  
2005 ◽  
Vol 59 (5) ◽  
pp. 514-518 ◽  
Author(s):  
Enos Tangke Arung ◽  
Keisuke Yoshikawa ◽  
Kuniyoshi Shimizu ◽  
Ryuichiro Kondo
Keyword(s):  
Inhibitory Activity ◽  
Melanoma Cells ◽  
B16 Melanoma ◽  
Mushroom Tyrosinase ◽  
Tyrosinase Inhibitor ◽  
Melanin Biosynthesis ◽  
B16 Melanoma Cells ◽  
Bioassay Guided Fractionation ◽  
Unstable Compound ◽  
Potent Inhibitory Activity

Abstract By means of bioassay-guided fractionation using mushroom tyrosinase, a geranylated stilbene, chlorophorin, was characterized as the principal tyrosinase inhibitor in the heartwood of Chlorophora excelsa (Moraceae). It inhibited the oxidation of L-tyrosine and DL-3,4-dihydroxyphenylalanine (DL-DOPA) due to mushroom tyrosinase and melanin biosynthesis on B16 melanoma cells. Chlorophorin, which is a slight yellowish compound, has previously been reported as an unstable compound in light. On the basis of this finding, a chlorophorin derivative [4-(3″,7″-dimethyloctyl)-2′,3,4′,5-tetrahydroxydihydrostilbene; hexahydrochlorophorin] which is colorless, obtained by the hydrogenation of chlorophorin with Pd/C, was also tested to develop a superior material for practical use. Hexahydrochlorophorin showed more potent inhibitory activity on tyrosinase and melanin biosynthesis, and lower cytotoxicity towards B16 melanoma cells than chlorophorin.

scholarly journals Azastilbene Analogs as Tyrosinase Inhibitors: New Molecules with Depigmenting Potential

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Larissa Lavorato Lima ◽  
Rebeca Mól Lima ◽  
Annelisa Farah da Silva ◽  
Antônio Márcio Resende do Carmo ◽  
Adilson David da Silva ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Tyrosinase Inhibitor ◽  
Tyrosinase Inhibition ◽  
Tyrosinase Inhibitory Activity ◽  
Qualitative And Quantitative ◽  
Phenolic Ring ◽  
Tyrosinase Inhibitors ◽  
Resveratrol Analogs ◽  
Better Than

This research has been an effort to develop synthetic resveratrol analogs in order to improve the depigmenting potential of natural resveratrol. Six resveratrol analogs were synthesized and tested for tyrosinase inhibitory activityin vitro, by qualitative and quantitative steps. The results showed the analogCas being the most powerful tyrosinase inhibitor (IA50= 65.67 ± 0.60 μg/mL), followed by the analogsB,E,F,A, andD, respectively. The analogCpresented a tyrosinase inhibition potential better than natural resveratrol (P<0.001). The best depigmenting activity was provided by the presence of hydroxyl in the orthoposition on the second phenolic ring.

Structure-based virtual screening, biological evaluation and biophysical study of novel Mcl-1 inhibitors

2020 ◽  
Vol 12 (14) ◽  
pp. 1293-1304 ◽  
Author(s):  
Jintong Du ◽  
Lulu Liu ◽  
Bo Liu ◽  
Jing Yang ◽  
Xuben Hou ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Protein Interactions ◽  
Salt Bridge ◽  
Biological Evaluation ◽  
Protein Protein Interactions ◽  
Promising Therapeutic Approach ◽  
Starting Point ◽  
Proliferation Activity ◽  
Biophysical Study ◽  
Good Starting Point

Aim: Targeting the protein–protein interactions (PPIs) associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Results: Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors M02 ( K i  = 5.4 μM) and M08 ( Ki = 0.53 μM) exhibit good selectivity against Bcl-2 and Bcl-xL. Compound M08 exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, 1H⁄15N HSQC NMR experiments suggested that compound M08 likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Conclusion: Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.

scholarly journals Non-Extensive Fragmentation of Natural Products and Pharmacophore-Based Virtual Screening as a Practical Approach to Identify Novel Promising Chemical Scaffolds

2021 ◽  
Vol 9 ◽  
Author(s):  
Andrés Felipe Vásquez ◽  
Alejandro Reyes Muñoz ◽  
Jorge Duitama ◽  
Andrés González Barrios
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Natural Product ◽  
Structural Diversity ◽  
Pharmacophore Modeling ◽  
Classical Type ◽  
Starting Point ◽  
Novel Drugs ◽  
Before And After ◽  
Good Starting Point

Fragment-based drug design (FBDD) and pharmacophore modeling have proven to be efficient tools to discover novel drugs. However, these approaches may become limited if the collection of fragments is highly repetitive, poorly diverse, or excessively simple. In this article, combining pharmacophore modeling and a non-classical type of fragmentation (herein called non-extensive) to screen a natural product (NP) library may provide fragments predicted as potent, diverse, and developable. Initially, we applied retrosynthetic combinatorial analysis procedure (RECAP) rules in two versions, extensive and non-extensive, in order to deconstruct a virtual library of NPs formed by the databases Traditional Chinese Medicine (TCM), AfroDb (African Medicinal Plants database), NuBBE (Nuclei of Bioassays, Biosynthesis, and Ecophysiology of Natural Products), and UEFS (Universidade Estadual de Feira de Santana). We then developed a virtual screening (VS) using two groups of natural-product-derived fragments (extensive and non-extensive NPDFs) and two overlapping pharmacophore models for each of 20 different proteins of therapeutic interest. Molecular weight, lipophilicity, and molecular complexity were estimated and compared for both types of NPDFs (and their original NPs) before and after the VS proceedings. As a result, we found that non-extensive NPDFs exhibited a much higher number of chemical entities compared to extensive NPDFs (45,355 vs. 11,525 compounds), accounting for the larger part of the hits recovered and being far less repetitive than extensive NPDFs. The structural diversity of both types of NPDFs and the NPs was shown to diminish slightly after VS procedures. Finally, and most interestingly, the pharmacophore fit score of the non-extensive NPDFs proved to be not only higher, on average, than extensive NPDFs (56% of cases) but also higher than their original NPs (69% of cases) when all of them were also recognized as hits after the VS. The findings obtained in this study indicated that the proposed cascade approach was useful to enhance the probability of identifying innovative chemical scaffolds, which deserve further development to become drug-sized candidate compounds. We consider that the knowledge about the deconstruction degree required to produce NPDFs of interest represents a good starting point for eventual synthesis, characterization, and biological activity studies.

Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

2020 ◽  
Author(s):  
Eleonora Diamanti ◽  
Inda Setyawati ◽  
Spyridon Bousis ◽  
leticia mojas ◽  
lotteke Swier ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design Synthesis ◽  
Screening Design ◽  
Starting Point ◽  
Wide Range ◽  
Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

scholarly journals Advances on the Implementation of Circular Economy Techniques in Rural Areas in Colombia under a Sustainable Development Framework

2021 ◽  
Vol 13 (7) ◽  
pp. 3816
Author(s):  
Javier Rodrigo-Ilarri ◽  
Camilo-A. Vargas-Terranova ◽  
María-Elena Rodrigo-Clavero ◽  
Paula-A. Bustos-Castro
Keyword(s):  
Sustainable Development ◽  
Waste Management ◽  
Circular Economy ◽  
Rural Areas ◽  
Development Framework ◽  
Starting Point ◽  
Management Plans ◽  
Good Starting Point ◽  
Depressed Regions ◽  
First Time

For the first time in the scientific literature, this research shows an analysis of the implementation of circular economy techniques under sustainable development framework in six municipalities with a depressed economy in Colombia. The analysis is based on solid waste data production at a local scale, the valuation of the waste for subsequent recycling, and the identification and quantification of the variables associated with the treatment and final disposal of waste, in accordance with the Colombian regulatory framework. Waste generation data are obtained considering three different scenarios, in which a comparison between the simulated values and those established in the management plans are compared. Important differences have been identified between the waste management programs of each municipality, specifically regarding the components of waste collection, transportation and disposal, participation of environmental reclaimers, and potential use of materials. These differences are fundamentally associated with the different administrative processes considered for each individual municipality. This research is a good starting point for the development of waste management models based on circular economy techniques, through the subsequent implementation of an office tool in depressed regions such as those studied.

scholarly journals Massiliamide, a cyclic tetrapeptide with potent tyrosinase inhibitory properties from the Gram-negative bacterium Massilia albidiflava DSM 17472T

2020 ◽  
Author(s):  
Andri Frediansyah ◽  
Jan Straetener ◽  
Heike Brötz-Oesterhelt ◽  
Harald Gross
Keyword(s):  
Absolute Configuration ◽  
Inhibitory Activity ◽  
Liquid Culture ◽  
Spectroscopic Analysis ◽  
2D Nmr ◽  
Negative Bacterium ◽  
Gram Negative ◽  
The Absolute ◽  
Potent Inhibitory Activity ◽  
Cyclic Tetrapeptide

AbstractA cyclic tetrapeptide, designated massiliamide, was isolated from the liquid culture of the Gram-negative bacterium Massilia albidiflava DSM 17472T. The structure was elucidated through extensive spectroscopic analysis, including HR-MS and 1D and 2D NMR experiments. The absolute configuration was determined using the Marfey´s method. Massiliamide showed potent inhibitory activity towards tyrosinase with an IC50 value of 1.15 µM and no cytotoxicity.

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