scholarly journals The Guanidine Pseudoalkaloids 10-Methoxy-Leonurine and Leonurine Act as Competitive Inhibitors of Tyrosinase

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 174
Author(s):  
Jang Hoon Kim ◽  
Hyun Hee Leem ◽  
Ga Young Lee
Keyword(s):  
Benzene Ring ◽  
Active Site ◽  
In Silico ◽  
Guanidine Group ◽  
Lead Compounds ◽  
In Silico Modeling ◽  
Competitive Inhibitors ◽  
Ic50 Values ◽  
Tyrosinase Inhibitors ◽  
Micromolar Range

Tyrosinase plays a key role in the production of melanin. A variety of industrial fields have shown interest in the development of tyrosinase inhibitors from plants. In this study, compounds 1–5 derived from Leonurus japonicas were evaluated to determine their ability to inhibit tyrosinase. Of these, 10-methoxy-leonurine (1) and leonurine (2) exhibited IC50 values of 7.4 ± 0.4 and 12.4 ± 0.8 μM, respectively, and acted as competitive inhibitors of tyrosinase, with Ki values in the micromolar range. In silico modeling revealed a guanidine group located in the inner cavity and a benzene ring docked within the active site of these compounds. These guanidine pseudoalkaloids show potential not only as tyrosinase inhibitors but also as lead compounds in new scaffolds for the development of novel inhibitors.

Correlating In Vitro Target-Oriented Screening and Docking: Inhibition of Matrix Metalloproteinases Activities by Flavonoids

Planta Medica ◽  
2017 ◽  
Vol 83 (11) ◽  
pp. 901-911 ◽  
Author(s):  
Lucia Crascì ◽  
Livia Basile ◽  
Annamaria Panico ◽  
Carmelo Puglia ◽  
Francesco Bonina ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
In Silico ◽  
In Silico Docking ◽  
Lead Compounds ◽  
Good Ability ◽  
Metalloprotease Inhibitors ◽  
Ic50 Values ◽  
Further Development

AbstractMetalloproteases are a family of zinc-containing endopeptidases involved in a variety of pathological disorders. The use of flavonoid derivatives as potential metalloprotease inhibitors has recently increased.Particular plants growing in Sicily are an excellent yielder of the flavonoids luteolin, apigenin, and their respective glycoside derivatives (7-O-rutinoside, 7-O-glucoside, and 7-O-glucuronide).The inhibitory activity of luteolin, apigenin, and their respective glycoside derivatives on the metalloproteases MMP-1, MMP-3, MMP-13, MMP-8, and MMP-9 was assessed and rationalized correlating in vitro target-oriented screening and in silico docking.The flavones apigenin, luteolin, and their respective glucosides have good ability to interact with metalloproteases and can also be lead compounds for further development. Glycones are more active on MMP-1, -3, -8, and -13 than MMP-9. Collagenases MMP-1, MMP-8, and MMP-13 are inhibited by compounds having rutinoside glycones. Apigenin and luteolin are inactive on MMP-1, -3, and -8, which can be interpreted as a better selectivity for both -9 and -13 peptidases. The more active compounds are apigenin-7-O-rutinoside on MMP-1 and luteolin-7-O-rutinoside on MMP-3. The lowest IC50 values were also found for apigenin-7-O-glucuronide, apigenin-7-O-rutinoside, and luteolin-7-O-glucuronide. The glycoside moiety might allow for a better anchoring to the active site of MMP-1, -3, -8, -9, and -13. Overall, the in silico data are substantially in agreement with the in vitro ones (fluorimetric assay).

scholarly journals In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

2020 ◽  
Author(s):  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Mohammed Ahmed ◽  
Deepsikha Kar ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Active Site ◽  
In Silico ◽  
3D Structure ◽  
Drug Repurposing ◽  
The Novel ◽  
Lead Compounds ◽  
Nucleotidyl Transferase ◽  
Domain Organisation ◽  
Novel Coronavirus ◽  
In Silico Characterization

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of the RdRp from the novel coronavirus – SARS-CoV2, provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, this study predicts that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds GTP and UTP at its proposed active site. Additionally, using molecular docking this study predicts the binding of five well characterized anti-microbial compounds at the NiRAN domain active site and their drug-likeliness and DFT properties. In line with the current global COVID-19 pandemic urgency, this study provides a new target and potential lead compounds for drug repurposing against SARS-CoV2.

Using in silico methods to obtain bioactive peptides of whey

2021 ◽  
pp. 32-35
Author(s):  
Ксения Александровна Рязанцева ◽  
Евгения Юрьевна Агаркова
Keyword(s):  
In Silico ◽  
Bioactive Peptides ◽  
Whey Proteins ◽  
Food Protein ◽  
Enzyme Preparations ◽  
Dpp Iv ◽  
Activity Modeling ◽  
In Silico Modeling ◽  
Ic50 Values ◽  
Beta Lactoglobulin

Целью данного исследования являлся скрининг биопептидов, высвобождаемых из белков молочной сыворотки с использованием базы данных BIOPEP. В задачи работы входили оценка сывороточных белков как потенциальных предшественников биоактивных пептидов с последующей оценкой их потенциальной биологической активности, моделирование ферментативного гидролиза и оценка полученного пептидного профиля. Объектами исследований являлись белки молочной сыворотки и ферментные препараты трипсин EC (3.4.21.4), химотрипсин EC (3.4.21.1) и алкалаза (EC 3.4.21.62). Методы исследований включали in silico анализ с использованием базы данных BIOPEP-UWM™. В результате исследований в бета-лактоглобулине была определена наибольшая частота встречаемости гипотензивных пептидов, ингибирующих ангиотензин-I-превращающий фермент (АПФ) (A=0,5528), и противодиабетических, ингибирующих дипептидилпептидазу IV (ДПП-IV) (A=0,6584), суммарная доля которых составила более 65 % среди всех потенциальных биопептидов. Наилучший результат при дальнейшем моделировании in silico гидролиза бета-лактоглобулина был получен с использованием трипсина, химотрипсина и алкалазы. Показано, что данные ферменты способствуют выделению пептидов с высокими значениями IC50: гипотензивные (VY [41-42] (IC50 = 7,1 мкМ), VF [80-81] (IC50 = 9,2 мкМ), VY [41-42] (IC50 = 7,1 мкМ), IIAEK [70-74] (IC50 = 63,7 мкМ), VR [122-123] (IC50 = 141мкМ) и противодиабетические (VL [91-92] (IC50 = 74 мкМ), IPAVF (IC50 = 44,7 мкМ), VR [122-123] (IC50 = 52,8 мкМ). Данные проведенного биоинформационного подхода определили условия для последующего воспроизведения на реальных пищевых белковых системах. The aim of this study was to screen for biopeptides released from whey proteins using the BIOPEP database. The tasks of the work included: assessment of whey proteins as potential precursors of bioactive peptides with subsequent assessment of their potential biological activity, modeling of enzymatic hydrolysis and assessment of the obtained peptide profile.The objects of the study were whey proteins and enzyme preparations trypsin EC (3.4.21.4), chymotrypsin EC (3.4.21.1) and Alcalase (EC 3.4.21.62). Research methods are included in silicoanalysis using the BIOPEP-UWM ™ database. As a result of studies on beta-lactoglobulin, the highest frequency of occurrence of antihypertensive peptides that inhibit angiotensin-I-converting enzyme (ACE) (A = 0.5528) and antidiabetic peptides that inhibit dipeptidyl peptidase IV (DPP-IV) (A = 0.6584) was obtained, the total share of which was more than 65 % among all potential biopeptides. The best result in further in silico modeling of beta-lactoglobulin hydrolysis was obtained using trypsin, chymotrypsin, and alkalase. These enzymes were shown to promote the release of peptides with high IC50 values: hypotensive (VY [41-42] (IC50 = 7.1 μM), VF [80-81] (IC50 = 9.2 μM), VY [41-42] (IC50 = 7.1 μM), IIAEK [70-74] (IC50 = 63.7 μM), VR [122-123] (IC50 = 141 μM) and antidiabetic (VL [91-92] (IC50 = 74 μM), IPAVF (IC50 = 44.7 μM), VR [122-123] (IC50 = 52.8 μM). The data of the bioinformatic approach carried out determined the conditions for subsequent reproduction on real food protein systems.

scholarly journals Screening of Human CYP1A2 and CYP3A4 Inhibitors from Seaweed In Silico and In Vitro

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 603
Author(s):  
Sung-Kun Yim ◽  
Kian Kim ◽  
SangHo Chun ◽  
TaeHawn Oh ◽  
WooHuk Jung ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
In Silico ◽  
Dependent Manner ◽  
Prosthetic Group ◽  
In Silico Modeling ◽  
Distal Surface ◽  
Ic50 Values ◽  
High Concentrations ◽  
Potential Inhibitors

Phenolic compounds and carotenoids are potential inhibitors of cytochrome P450s. Sixteen known compounds, phenolic compounds and carotenoids from seaweed were examined for potential inhibitory capacity against CYP1A2 and CYP3A4 in silico and in vitro. Morin, quercetin, and fucoxanthin inhibited the enzyme activity of CYP1A2 and CYP3A4 in a dose-dependent manner. The IC50 values of morin, quercetin, and fucoxanthin were 41.8, 22.5, and 30.3 μM for CYP1A2 and 86.6, 16.1, and 24.4 μM for CYP3A4, respectively. Siphonaxanthin and hesperidin did not show any significant effect on CYP1A2, but they slightly inhibited CYP3A4 activity at high concentrations. In silico modeling of CYP’s binding site revealed that the potential inhibitors bound in the cavity located above the distal surface of the heme prosthetic group through the 2a or 2f channel of CYPs. This study presents an approach for quickly predicting CYP inhibitory activity and shows the potential interactions of compounds and CYPs through in silico modeling.

The source of hERG IC50 values (manual vs. automated patch clamp) may influence in silico modeling

2015 ◽  
Vol 75 ◽  
pp. 167
Author(s):  
Jutta Rohrbacher ◽  
Bruce P. Damiano ◽  
Ihab G. Girgis ◽  
Michael K. Pugsley ◽  
Ard Teisman ◽  
...  
Keyword(s):  
Patch Clamp ◽  
In Silico ◽  
In Silico Modeling ◽  
Ic50 Values ◽  
Automated Patch Clamp

scholarly journals Slow-Binding Inhibition of Tyrosinase by Ecklonia cava Phlorotannins

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 359 ◽  
Author(s):  
Jang Hoon Kim ◽  
Sunggun Lee ◽  
Saerom Park ◽  
Ji Soo Park ◽  
Young Ho Kim ◽  
...  
Keyword(s):  
Active Site ◽  
Time Course ◽  
Enzyme Reaction ◽  
Single Step ◽  
Ecklonia Cava ◽  
Binding Mechanism ◽  
Skin Whitening ◽  
Binding Inhibition ◽  
Ic50 Values ◽  
Tyrosinase Inhibitors

Tyrosinase inhibitors improve skin whitening by inhibiting the formation of melanin precursors in the skin. The inhibitory activity of seven phlorotannins (1–7), triphlorethol A (1), eckol (2), 2-phloroeckol (3), phlorofucofuroeckol A (4), 2-O-(2,4,6-trihydroxyphenyl)-6,6′-bieckol (5), 6,8′-bieckol (6), and 8,8′-bieckol (7), from Ecklonia cava was tested against tyrosinase, which converts tyrosine into dihydroxyphenylalanine. Compounds 3 and 5 had IC50 values of 7.0 ± 0.2 and 8.8 ± 0.1 μM, respectively, in competitive mode, with Ki values of 8.2 ± 1.1 and 5.8 ± 0.8 μM. Both compounds showed the characteristics of slow-binding inhibitors over the time course of the enzyme reaction. Compound 3 had a single-step binding mechanism and compound 5 a two-step-binding mechanism. With stable AutoDock scores of −6.59 and −6.68 kcal/mol, respectively, compounds 3 and 5 both interacted with His85 and Asn260 at the active site.

scholarly journals In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1340 ◽  
Author(s):  
Jakub Chlebek ◽  
Jan Korábečný ◽  
Rafael Doležal ◽  
Šárka Štěpánková ◽  
Daniel Pérez ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Binding Mode ◽  
Brain Barrier ◽  
In Silico Docking ◽  
Lead Compounds ◽  
Blood Brain ◽  
Type Pattern ◽  
Ic50 Values

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman’s spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood–brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer’s disease.

scholarly journals Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6004
Author(s):  
Anusree Venkidath ◽  
Jong Min Oh ◽  
Sanal Dev ◽  
Elham Amin ◽  
Shebina P. Rasheed ◽  
...  
Keyword(s):  
Mao B ◽  
Lead Compounds ◽  
Small Series ◽  
Ic50 Value ◽  
Competitive Inhibitors ◽  
Docking Approach ◽  
Ic50 Values ◽  
Dual Inhibitors ◽  
Better Than

A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

scholarly journals Identification of amino acid networks governing catalysis in the closed complex of class I terpene synthases

2016 ◽  
Vol 113 (8) ◽  
pp. E958-E967 ◽  
Author(s):  
Patrick Schrepfer ◽  
Alexander Buettner ◽  
Christian Goerner ◽  
Michael Hertel ◽  
Jeaphianne van Rijn ◽  
...  
Keyword(s):  
Active Site ◽  
In Silico ◽  
Class I ◽  
Terpene Synthase ◽  
Terpene Synthases ◽  
Substrate Analogs ◽  
Inactive Form ◽  
In Silico Modeling ◽  
Site Localization ◽  
Reaction Cascades

Class I terpene synthases generate the structural core of bioactive terpenoids. Deciphering structure–function relationships in the reactive closed complex and targeted engineering is hampered by highly dynamic carbocation rearrangements during catalysis. Available crystal structures, however, represent the open, catalytically inactive form or harbor nonproductive substrate analogs. Here, we present a catalytically relevant, closed conformation of taxadiene synthase (TXS), the model class I terpene synthase, which simulates the initial catalytic time point. In silico modeling of subsequent catalytic steps allowed unprecedented insights into the dynamic reaction cascades and promiscuity mechanisms of class I terpene synthases. This generally applicable methodology enables the active-site localization of carbocations and demonstrates the presence of an active-site base motif and its dominating role during catalysis. It additionally allowed in silico-designed targeted protein engineering that unlocked the path to alternate monocyclic and bicyclic synthons representing the basis of a myriad of bioactive terpenoids.

scholarly journals Discovery of Bifunctional Anti-DPP-IV and Anti-ACE Peptides from Housefly Larval Proteins After In silico Gastrointestinal Digestion

2021 ◽  
Vol 12 (4) ◽  
pp. 4929-4944
Keyword(s):  
Active Site ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Dipeptidyl Peptidase ◽  
Dpp Iv ◽  
Single Function ◽  
Competitive Inhibitors ◽  
Potential Applications ◽  
Gi Absorption ◽  
Proteins And Peptides

Proteins and peptides of housefly larvae (HFL) have potential applications in food and therapy. The fate of HFL proteins following human gastrointestinal (GI) digestion is unknown. This study adopted a computational approach to discover peptides released from HFL proteins upon GI digestion. In silico digestion of eight major HFL proteins released 783 peptides. This comprised 243 peptides exhibiting 13 types of bioactivities. Ninety-two single-function peptides exhibiting anti-dipeptidyl peptidase IV (anti-DPP-IV), anti-dipeptidyl peptidase III, anti-angiotensin converting enzyme (anti-ACE), or antioxidant activity were found. Sixty-three multi-function peptides, encompassing 32 bifunctional anti-DPP-IV and anti-ACE peptides, were found. Further screening led to five non-toxic, non-allergenic, high-GI-absorption bifunctional dipeptides: AF, GW, GY, PH, and VF. Molecular docking found the dipeptides to interact with the active site of DPP-IV through hydrophobic interactions. Only GW and VF could bind to the active site of ACE. Thus, the five dipeptides are competitive inhibitors of DPP-IV. GW and VF are potential competitive inhibitors of ACE, whereas AF, GY, and PH are non-competitive inhibitors. Overall, GI digestion could liberate numerous single- and multi-function peptides from HFL proteins. Hence, HFL proteins can be tapped for potential applications in antidiabetic and antihypertension functional food and therapy.

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