Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.

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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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Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190906101326 ◽

2019 ◽

Vol 18 (8) ◽

pp. 643-654 ◽

Cited By ~ 11

Author(s):

Reeta ◽

Seung Cheol Baek ◽

Jae Pil Lee ◽

T.M. Rangarajan ◽

Ayushee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Monoamine Oxidase ◽

Target Prediction ◽

Inhibitory Effect ◽

Monoamine Oxidase A ◽

Mao B ◽

Drug Molecules ◽

Ic50 Value ◽

Ic50 Values

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B. Objective: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer’s Disease (AD). Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed. Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively. Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

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

Molecules ◽

10.3390/molecules26196004 ◽

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.

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Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

Molecules ◽

10.3390/molecules25173896 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3896

Author(s):

Geum Seok Jeong ◽

Myung-Gyun Kang ◽

Joon Yeop Lee ◽

Sang Ryong Lee ◽

Daeui Park ◽

...

Keyword(s):

Monoamine Oxidase ◽

Binding Affinity ◽

Competitive Inhibitor ◽

Glycyrrhiza Uralensis ◽

Form Hydrogen Bond ◽

Docking Simulations ◽

Mao B ◽

Mao A ◽

Ic50 Values ◽

Noncompetitive Inhibitor

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

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Thermodynamics of water mediating protein-ligand interactions in cytochrome P450cam: a molecular dynamics study

Biophysical Journal ◽

10.1016/s0006-3495(95)79955-6 ◽

1995 ◽

Vol 69 (3) ◽

pp. 810-824 ◽

Cited By ~ 59

Author(s):

V. Helms ◽

R.C. Wade

Keyword(s):

Molecular Dynamics ◽

Cytochrome P450cam ◽

Protein Ligand Interactions ◽

Ligand Interactions

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Using molecular docking and molecular dynamics to investigate protein-ligand interactions

Modern Physics Letters B ◽

10.1142/s0217984921300027 ◽

2021 ◽

Vol 35 (08) ◽

pp. 2130002

Author(s):

Connor J. Morris ◽

Dennis Della Corte

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Drug Discovery ◽

State Of The Art ◽

Ligand Complex ◽

Protein Ligand Interactions ◽

Art Methods ◽

Ligand Interactions ◽

Docking Calculations ◽

Ligand Bond

Molecular docking and molecular dynamics (MD) are powerful tools used to investigate protein-ligand interactions. Molecular docking programs predict the binding pose and affinity of a protein-ligand complex, while MD can be used to incorporate flexibility into docking calculations and gain further information on the kinetics and stability of the protein-ligand bond. This review covers state-of-the-art methods of using molecular docking and MD to explore protein-ligand interactions, with emphasis on application to drug discovery. We also call for further research on combining common molecular docking and MD methods.

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Exploring Protein-Protein and Protein-Ligand Interactions in the Immune System using Molecular Dynamics and Continuum Electrostatics

Current Physical Chemistry ◽

10.2174/1877946811202040324 ◽

2012 ◽

Vol 2 (4) ◽

pp. 324-343 ◽

Cited By ~ 16

Author(s):

Chris A. Kieslich ◽

Phanourios Tamamis ◽

Ronald D. Gorham Jr. ◽

Aliana Lopez de Victoria ◽

Noriko U. Sausman ◽

...

Keyword(s):

Molecular Dynamics ◽

Immune System ◽

Continuum Electrostatics ◽

Protein Ligand Interactions ◽

Ligand Interactions

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Enlighten2: molecular dynamics simulations of protein–ligand systems made accessible

Bioinformatics ◽

10.1093/bioinformatics/btaa643 ◽

2020 ◽

Vol 36 (20) ◽

pp. 5104-5106

Author(s):

Kirill Zinovjev ◽

Marc W van der Kamp

Keyword(s):

Molecular Dynamics ◽

Expert Knowledge ◽

Structural Data ◽

Md Simulations ◽

Enzyme Engineering ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Dynamics Simulations ◽

User Friendly ◽

Dynamical Information

Abstract Motivation Experimental structural data can allow detailed insight into protein structure and protein–ligand interactions, which is crucial for many areas of bioscience, including drug design and enzyme engineering. Typically, however, little more than a static picture of protein–ligand interactions is obtained, whereas dynamical information is often required for deeper understanding and to assess the effect of mutations. Molecular dynamics (MD) simulations can provide such information, but setting up and running these simulations is not straightforward and requires expert knowledge. There is thus a need for a tool that makes protein–ligand simulation easily accessible to non-expert users. Results We present Enlighten2: efficient simulation protocols for protein–ligand systems alongside a user-friendly plugin to the popular visualization program PyMOL. With Enlighten2, non-expert users can straightforwardly run and visualize MD simulations on protein–ligand models of interest. There is no need to learn new programs and all underlying tools are free and open source. Availability and implementation The Enlighten2 Python package and PyMOL plugin are free to use under the GPL3.0 licence and can be found at https://enlighten2.github.io. We also provide a lightweight Docker image via DockerHub that includes Enlighten2 with all the required utilities.

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An Investigation of Small GTPases in relation to Liver Tumorigenesis Using Traditional Chinese Medicine

BioMed Research International ◽

10.1155/2014/428210 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Tzu-Chieh Hung ◽

Wen-Yuan Lee ◽

Kuen-Bao Chen ◽

Yueh-Chiu Chan ◽

Calvin Yu-Chian Chen

Keyword(s):

Molecular Dynamics ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Hydrophobic Interactions ◽

Small Gtpases ◽

Ligand Interaction ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Protein Ligand Interaction ◽

Better Than

Recently, an important topic of liver tumorigenesis had been published in 2013. In this report, Ras and Rho had defined the relation of liver tumorigenesis. The traditional Chinese medicine (TCM) database has been screened for molecular compounds by simulating molecular docking and molecular dynamics to regulate Ras and liver tumorigenesis. Saussureamine C, S-allylmercaptocysteine, and Tryptophan are selected based on the highest docking score than other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. Based on the docking poses, hydrophobic interactions, and hydrogen bond variations, this research surmises are the main regions of important amino acids in Ras. In addition to the detection of TCM compound efficacy, we suggest Saussureamine C is better than the others for protein-ligand interaction.

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