(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 µM for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 µM). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 µM) but very weakly inhibited butyrylcholinesterase and β-secretase. Compound 5MM had a Ki value of 2.45 μM and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (−6.8 kcal/mol) than hMAO-B (−6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (−6.6 kcal/mol) and hMAO-B (−5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 Å), while the R-form interacted with the Asn181 residue (2.375 Å). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski’s five rules and showed high gastrointestinal absorption and blood–brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

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Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules ◽

10.3390/molecules26113264 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3264

Author(s):

Aathira Sujathan Nair ◽

Jong-Min Oh ◽

Vishal Payyalot Koyiparambath ◽

Sunil Kumar ◽

Sachithra Thazhathuveedu Sudevan ◽

...

Keyword(s):

Molecular Dynamics ◽

Monoamine Oxidase ◽

Phenyl Ring ◽

Competitive Inhibitor ◽

Selectivity Index ◽

Monoamine Oxidase A ◽

Mao B ◽

Ic50 Value ◽

The Central Nervous System ◽

Inhibitory Activities

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

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MODULATORY ANTI- DIARRHEAL EFFECTS OF ASCORBIC ACID IN SWISS ALBINO MICE

Khulna University Studies ◽

10.53808/kus.2021.18.01.2103-l ◽

2021 ◽

Vol 18 (1) ◽

pp. 9-17

Keyword(s):

Ascorbic Acid ◽

Adrenergic Receptor ◽

Castor Oil ◽

Docking Study ◽

Binding Affinities ◽

Molecular Docking Study ◽

Receptor Blocking ◽

Swiss Mice ◽

Mixed Groups ◽

The Impact

Ascorbic acid (AA) has been reported for the management of diarrhea. The anti-diarrheal potential and modulatory activities of AA on some commonly used anti-diarrheal drugs were investigated. For this purpose, the activities of AA on castor oil-induced diarrhea in Swiss mice were examined. As standard anti-diarrheal agents, we used prazosin, propranolol, loperamide, and nifedipine with or without AA. The results revealed that AA at 25 mg/kg (i.p.) and all other standard drugs exhibited significant (p < 0.05) diarrheal attenuating activities in mice. However, the impact was more pronounced in the loperamide and propranolol groups. AA administrated with prazosin and propranolol had a higher rate of latent periods and a lower rate of diarrheic secretion during the study period (4 h) than that of the other single or mixed groups. Furthermore, a molecular docking study illustrated that AA displayed good binding affinities with (α1) (–5.2 Kcal/mol), α2b (–5.4 Kcal/mol), α2c (-5.6 Kcal/mol), β1(–5.3 Kcal/mol) and β2(–6.4 Kcal/mol) adrenoceptors. Of note, AA exerted a significant anti-diarrheal effect and it was seen to modulate the anti-diarrheal effects of α- and β-adrenergic receptor blocking agents in Swiss mice.

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Synthesis of Thymidine Phosphorylase Inhibitor Based on Quinoxaline Derivatives and Their Molecular Docking Study

Molecules ◽

10.3390/molecules24061002 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1002 ◽

Cited By ~ 3

Author(s):

Noor Almandil ◽

Muhammad Taha ◽

Rai Farooq ◽

Amani Alhibshi ◽

Mohamed Ibrahim ◽

...

Keyword(s):

Molecular Docking ◽

Thymidine Phosphorylase ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Substitution Pattern ◽

Structure Activity ◽

Ic50 Value ◽

Quinoxaline Derivatives ◽

Better Than

We have synthesized quinoxaline analogs (1–25), characterized by 1H-NMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent compound among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21 and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure-activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.

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Synthesis, Molecular Docking, and Evaluation of Some New Curcumin Analogs as Antimalarial Agents

Indonesian Journal of Chemistry ◽

10.22146/ijc.57646 ◽

2021 ◽

Vol 21 (2) ◽

pp. 452

Author(s):

Endang Astuti ◽

Tri Joko Raharjo ◽

Putra Boang Manalu ◽

Ilham Satria Putra ◽

Stephanus Satria Waskitha ◽

...

Keyword(s):

Molecular Docking ◽

Aldol Condensation ◽

Antimalarial Activity ◽

Docking Study ◽

Docking Studies ◽

Curcumin Analog ◽

Molecular Docking Study ◽

Antimalarial Agents ◽

Curcumin Analogs ◽

Ic50 Value

This research involves the synthesis, antimalarial evaluation, and molecular docking of several curcumin analogs. A total of six curcumin analog compounds were synthesized using aldol condensation using hydrochloric acid and sodium hydroxide catalysts. The synthesized compounds were elucidated using FTIR, 1H-NMR, 13C-NMR, and LC-MS/MS. Subsequently, all curcumin analogs were tested as an antimalarial agent against Plasmodium falciparum 3D7 strain, and their mechanism of action was evaluated through a molecular docking study. Six curcumin analogs, i.e. 2,6-bis(2-hydroxybenzylidene)cyclohexanone; 2,6-bis(2-hydroxybenzylidene)cyclopentanone; 1.5-bis(2-hydroxyphenyl)penta-1,4-diene-3-one; 2,6-bis(3-hydroxybenzylidene)cyclo-hexanone; 2,6-bis(3-hydroxybenzylidene)cyclopentanone; and 1,5-bis(3-hydroxy-phenyl)penta-1,4-diene-3-one have been successfully synthesized. In addition, 2,6-bis(2-hydroxybenzylidene) cyclopentanone demonstrated the lowest IC50 value and binding affinity of 0.04 µM and -7.6 kcal/mol, respectively. Based on molecular docking studies, this compound also showed the most potent antimalarial activity targeted at PfATP6.

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Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666191015130037 ◽

2020 ◽

Vol 20 (9) ◽

pp. 788-800 ◽

Cited By ~ 2

Author(s):

Sobhi M. Gomha ◽

Zeinab A. Muhammad ◽

Elham Ezz El-Arab ◽

Amira M. Elmetwally ◽

Abdelaziz A. El-Sayed ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Docking ◽

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

Design Synthesis ◽

Reference Drug ◽

Ic50 Value

Objective: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. Methods: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. Results: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM). Conclusion: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

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Synthesis of 2-(4-hydroxyphenyl)ethyl 3,4,5-Trihydroxybenzoate and Its Inhibitory Effect on Sucrase and Maltase

Processes ◽

10.3390/pr8121603 ◽

2020 ◽

Vol 8 (12) ◽

pp. 1603

Author(s):

Wen-Tai Li ◽

Yu-Hsuan Chuang ◽

Jiahn-Haur Liao ◽

Jung-Feng Hsieh

Keyword(s):

Active Site ◽

Docking Study ◽

Competitive Inhibitor ◽

Inhibitory Effect ◽

Kinetics Study ◽

Amino Acid Residues ◽

Inhibition Kinetics ◽

Molecular Docking Study ◽

Hydrogen Bond Interactions ◽

Glucosidase Inhibitors

We report on the synthesis of an active component, 2-(4-hydroxyphenyl)ethyl 3,4,5-trihydroxybenzoate (HETB), from Rhodiola crenulata. Subsequent analysis revealed that HETB exhibits α-glucosidase inhibitory activities on maltase and sucrase, with potency exceeding that of the known α-glucosidase inhibitors (voglibose and acarbose). An inhibition kinetics study revealed that HETB, acarbose, and voglibose bind to maltase and sucrase, and HETB was shown to be a strong competitive inhibitor of maltase and sucrase. In a molecular docking study based on the crystal structure of α-glucosidase from Saccharomyces cerevisiae, we revealed the HETB binding in the active site of maltase via hydrogen-bond interactions with five amino acid residues: Ser 240, Asp 242, Glu 277, Arg 315, and Asn 350. For HETB docked to the sucrase active site, seven hydrogen bonds (with Asn 114, Glu 148, Gln 201, Asn 228, Gln 381, Ile 383, and Ser 412) were shown.

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Potent and Selective Inhibitors of Human Monoamine Oxidase A from an Endogenous Lichen Fungus Diaporthe mahothocarpus

Journal of Fungi ◽

10.3390/jof7100876 ◽

2021 ◽

Vol 7 (10) ◽

pp. 876

Author(s):

Geum Seok Jeong ◽

Prima F. Hillman ◽

Myung-Gyun Kang ◽

Sungbo Hwang ◽

Jong-Eun Park ◽

...

Keyword(s):

Hydrogen Bond ◽

Tight Binding ◽

Docking Studies ◽

Monoamine Oxidase A ◽

Binding Affinities ◽

Hydrogen Bond Interaction ◽

Bond Interaction ◽

Ic50 Values ◽

Inhibitory Activities ◽

Lichen Fungus

Using 126 endogenous lichen fungus (ELF) extracts, inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) were evaluated. Among them, extract ELF29 of the endogenous fungus Diaporthe mahothocarpus of the lichen Cladonia symphycarpia showed the highest inhibitory activity against hMAO-A. Compounds alternariol (AT), 5′-hydroxy-alternariol (HAT), and mycoepoxydiene (MED), isolated from the extract, had potent inhibitory activities against hMAO-A with IC50 values of 0.020, 0.31, and 8.68 µM, respectively. AT, HAT, and MED are reversible competitive inhibitors of hMAO-A with Ki values of 0.0075, 0.116, and 3.76 µM, respectively. The molecular docking studies suggested that AT, HAT, and MED had higher binding affinities for hMAO-A (−9.1, −6.9, and −5.6 kcal/mol, respectively) than for hMAO-B (−6.3, −5.2, and −3.7 kcal/mol, respectively). The relative tight binding might result from a hydrogen bond interaction of the three compounds with a Tyr444 residue in hMAO-A, whereas no hydrogen bond interaction was proposed in hMAO-B. In silico pharmacokinetics, the three compounds showed high gastrointestinal absorption without violating Lipinski’s five rules, but only MED showed high probability to cross the blood–brain barrier. These results suggest that AT, HAT, and MED are candidates for treating neuropsychiatric disorders, such as depression and cardiovascular disease.

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Synthesis and molecular docking study of piperazine derivatives as potent inhibitor of thymidine phosphorylase

Bioorganic Chemistry ◽

10.1016/j.bioorg.2018.03.026 ◽

2018 ◽

Vol 78 ◽

pp. 324-331 ◽

Cited By ~ 7

Author(s):

Imad Uddin ◽

Muhammad Taha ◽

Fazal Rahim ◽

Abdul Wadood

Keyword(s):

Molecular Docking ◽

Thymidine Phosphorylase ◽

Potent Inhibitor ◽

Docking Study ◽

Molecular Docking Study ◽

Piperazine Derivatives

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Synthesis of Diabetic II Inhibitors Based on 2-mercaptobenzimidazole and their Molecular Docking Study

10.20944/preprints201911.0375.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Muhammad Taha ◽

Fazal Rahim ◽

Shawkat Hayat ◽

Manikandan Selvaraj ◽

Rai Khalid Farooq ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Binding Mode ◽

Alpha Amylase ◽

Variable Degree ◽

Molecular Docking Study ◽

Standard Drug ◽

Ic50 Value ◽

Ic50 Values ◽

Inhibitory Potential

In the search of potent α-amylase inhibitors, we have synthesized seventeen derivatives of 2-mercaptobenzimidazole bearing sulfonamide (1-17) and evaluated for their α-amylase inhibitory potential. All compounds display a variable degree of α-amylase activity having IC50 values ranging between 0.90 ± 0.05 to 11.20 ± 0.30 µM when compared with the standard drug acarbose having IC50 value 1.70 ± 0.10 µM. Compound 1, 2, 11, 12 and 14 having IC50 values 1.40 ± 0.10, 1.30 ± 0.05, 0.90 ± 0.05, 1.60 ± 0.05 and 1.60 ± 0.10 µM respectively were found many folds better than the standard drug acarbose. The remaining analogs showed good inhibitory potentials. All the synthesized compounds were characterized by HREI-MS, 1H and 13C-NMR. Structure activity relationship (SAR) has been recognized for all newly synthesized analogs. Through molecular docking study, binding mode of active analogs with α-amylase enzyme was confirmed.

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Tripeptides from Allium subhirsitum L. extracts: Pharmacokinetics properties, toxicity prediction and in silico study against SARS-CoV-2 enzymes and pro-inflammatory proteins

Cellular and Molecular Biology ◽

10.14715/cmb/2021.67.4.17 ◽

2022 ◽

Vol 67 (4) ◽

pp. 143-162

Author(s):

Mejdi Snoussi ◽

Emira Noumi ◽

Amor Mosbah ◽

Alaeddine Redissi ◽

Mohd Saeed ◽

...

Keyword(s):

Interleukin 1 ◽

Docking Study ◽

Strong Interactions ◽

Binding Affinities ◽

Toxicity Prediction ◽

Molecular Docking Study ◽

Multiplication Cycle ◽

In Silico Study ◽

Antiviral Activities ◽

Inflammatory Proteins

Developing new prophylactic and therapeutic agents with broad-spectrum antiviral activities is urgently needed to combat emerging human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since no available clinically antiviral drugs have been approved to eradicate COVID-19 as of the writing of this report, this study aimed to investigate bioactive short peptides from Allium subhirsutum L. (Hairy garlic) extracts identified through HR-LC/MS analysis that could potentially hinder the multiplication cycle of SARS-CoV-2 via molecular docking study. The obtained promising results showed that the peptides (Asn-Asn-Asn) possess the highest binding affinities of -8.4 kcal/mol against S protein, (His-Phe-Gln) of -9.8 kcal/mol and (Gln-His-Phe) of -9.7 kcal/mol towards hACE2, (Thr-Leu-Trp) of -10.3 kcal/mol and (Gln-Phe-Tyr) of -9.8 kcal/mol against furin. Additionally, the identified peptides show strong interactions with the targeted and pro-inflammatory ranging from -8.1 to -10.5 kcal/mol for NF−κB-inducing kinase (NIK), from -8.2 to -10 kcal/mol for phospholipase A2 (PLA2), from -8.0 to -10.7 kcal/mol for interleukin-1 receptor-associated kinase 4 (IRAK-4), and from -8.6 to -11.6 kcal/mol for the cyclooxygenase 2 (COX2) with Gln-Phe-Tyr model seems to be the most prominent. Results from pharmacophore, drug-likeness and ADMET prediction analyses clearly evidenced the usability of the peptides to be developed as an effective drug, beneficial for COVID-19 treatment.

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