Identification of butyrylcholinesterase and monoamine oxidase B targeted ligands and their putative application in Alzheimer’s treatment: A computational strategy

2021 ◽  
Vol 27 ◽  
Author(s):  
Nasimudeen R Jabir ◽  
Md Tabish Rehman ◽  
Shams Tabrez ◽  
Raed F. Alserihi ◽  
Mohamed F AlAjmi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Monoamine Oxidase ◽  
Monoamine Oxidase A ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Computational Screening ◽  
Mao A

Background: With the burgeoning worldwide aging population, the incidence of Alzheimer’s disease (AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase) and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes namely butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly meet the unmet medical need of better AD treatment. Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAO-B using PyRx-Python prescription 0.8. The visualization of active interaction of studied compounds with targeted proteins was performed by Discovery Studio 2020 (BIOVIA). Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to -11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand 6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and -10.4 kcal mol respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed the formation of a stable complex. Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD drugs generated on this chemical scaffold.

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

Molecules ◽  
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.

scholarly journals Computer simulation of complex of lysine dendrigraft with molecules of therapeutic KED peptide

2019 ◽  
Vol 24 ◽  
pp. 02008
Author(s):  
Igor Neelov ◽  
Valerii Bezrodnyi ◽  
Anna Marchenko ◽  
Emil Fatullaev ◽  
Sofia Miktaniuk
Keyword(s):  
Molecular Dynamics ◽  
Computer Simulation ◽  
Molecular Dynamics Simulation ◽  
Complex Formation ◽  
Simulation Method ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Target Organs ◽  
Therapeutic Peptides ◽  
Drug And Gene Delivery

Lysine dendrimers and dendrigrafts are often used in biomedicine for drug and gene delivery to different target organs or cells. In present paper the possibility of complex formation by lysine dendrigraft and 16 molecules of therapeutic KED peptide was investigated using molecular dynamics simulation method. A system containing of one dendrigraftt and 16 KED peptides in water were studied. It was shown that stable complex consisting of the dendrigraft and the peptide molecules formed and structure of this complex was studied. Similar complexes could be used in future for delivery of other therapeutic peptides to target organs.

scholarly journals High-Throughput Virtual Screening, Molecular Dynamics Simulation, and Enzyme Kinetics Identified ZINC84525623 as a Potential Inhibitor of NDM-1

2019 ◽  
Vol 20 (4) ◽  
pp. 819 ◽  
Author(s):  
Md Rehman ◽  
Mohamed AlAjmi ◽  
Afzal Hussain ◽  
Gulam Rather ◽  
Meraj Khan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Enzyme Kinetics ◽  
High Throughput ◽  
Md Simulation ◽  
Dynamics Simulation ◽  
Multi Drug Resistance ◽  
Stable Complex ◽  
High Throughput Virtual Screening

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene blaNDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be −11.234 kcal/mol, and 1.74 × 108 M−1 respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.

Are Coumarin Derivatives The New Keys in Depression Treatment? In silico Key-lock Fitting Analysis of Coumarin Derivatives with Monoamine Oxidase-A

2020 ◽  
Vol 7 ◽  
Author(s):  
Dilara Karaman ◽  
Kemal YELEKCI ◽  
Serkan ALTUNTAS
Keyword(s):  
Monoamine Oxidase ◽  
Protein Interactions ◽  
In Silico ◽  
Monoamine Oxidase A ◽  
Coumarin Derivatives ◽  
Discovery Studio ◽  
Mao B ◽  
Drug Candidates ◽  
Mao A ◽  
Molecular Modeling Studies

The research of ligand-protein interactions with in silico molecular modeling studies on the atomic level gives an opportunity to be understood the pharmacokinetic metabolism of anti-depressant drug candidates. Monoamine oxidase (MAO) enzymes are important targets for the treatment of depressive disorder. MAOs have two isoforms as MAO-A and MAO-B being responsible for catalyzing of neurological amines. In this study a new series of coumarin derivatives were designed for selective and reversible inhibition of MAO-A enzyme. 3rd, 5th and 7th positions were selected to be placed of five different side groups. Docking procedures of each ligand in M series of these novel 125 compounds were executed with 10 runs by using AutoDock4.2 software. Docking results were analyzed via Discovery Studio 3.1 (Biovia Inc.). The most promising compounds were M118 and M123 according to selectivity index, SI (MAO-B/MAO-A)=180 fold and 209 fold and Ki values 7.25 nM and 12.01 nM, respectively. Overall, the current study provided significant knowledge for the development of new anti-depressant drugs.

scholarly journals Isolation and Biological Evaluation of Prenylated Flavonoids from Maclura pomifera

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yerkebulan Orazbekov ◽  
Mohamed A. Ibrahim ◽  
Serjan Mombekov ◽  
Radhakrishnan Srivedavyasasri ◽  
Ubaidilla Datkhayev ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Opioid Receptors ◽  
Cannabinoid Receptors ◽  
Biological Evaluation ◽  
Monoamine Oxidase A ◽  
Moderate Activity ◽  
Significant Activity ◽  
Mao B ◽  
Maclura Pomifera ◽  
Mao A

Phytochemical analysis of the ethanolic extract of Maclura pomifera fruits yielded four new compounds (I–IV) along with eleven known compounds (V–XV). The crude extract exhibited significant activity towards cannabinoid receptors (CB1: 103.4% displacement; CB2: 68.8% displacement) and possibly allosteric interaction with δ and μ opioid receptors (−49.7 and −53.8% displacement, resp.). Compound I was found to be possibly allosteric for κ and μ opioid receptors (−88.4 and −27.2% displacement, resp.) and showed moderate activity (60.5% displacement) towards CB1 receptor. Compound II exhibited moderate activity towards cannabinoid receptors CB1 and CB2 (47.9 and 42.3% displacement, resp.). The known compounds (V–VIII) exhibited prominent activity towards cannabinoid receptors: pomiferin (V) (IC50 of 2.110 and 1.318 μM for CB1 and CB2, resp.), auriculasin (VI) (IC50 of 8.923 μM for CB1), warangalone (VII) (IC50 of 1.670 and 4.438 μM for CB1 and CB2, resp.), and osajin (VIII) (IC50 of 3.859 and 7.646 μM for CB1 and CB2, resp.). The isolated compounds were also tested for inhibition of human monoamine oxidase-A and monoamine oxidase-B enzymes activities, where all the tested compounds showed fewer inhibitory effects on MAO-A compared to MAO-B activities: auriculasin (VI) (IC50 of 1.91 and 45.98 μM for MAO-B and MAO-A, resp.).

scholarly journals Histochemical investigation of criteria for the distinction between monoamine oxidase A and B in various species.

1984 ◽  
Vol 32 (6) ◽  
pp. 667-673 ◽  
Author(s):  
E Uchida ◽  
G B Koelle
Keyword(s):  
Dorsal Root Ganglion ◽  
Monoamine Oxidase ◽  
Dorsal Root ◽  
Monoamine Oxidase A ◽  
Rat Tissues ◽  
Histochemical Investigation ◽  
Mao B ◽  
Total Inhibition ◽  
Mao A ◽  
Cervical Ganglion

The superior cervical ganglion (SCG), pineal body (PB), and liver (L) of the rat, rabbit and cat were stained for monoamine oxidase (MAO) A and B by the tetranitro blue tetrazolium (TNBT) and coupled peroxidase ( PerOx ) methods, using 5-hydroxytryptamine (5HT), tryptamine ( Tryp ), tyramine (Tyr), and benzylamine (Bz) as substrates, and clorgyline (Cl) and deprenyl (Dep), both at 10(-7) M, as selective inhibitors. The nodose ganglion (NG) and dorsal root ganglion (DRG) of the rabbit and cat were also studied. The results with rat tissues were consistent with published quantitative findings (SCG, MAO-A much greater than B; PB, MAO-A less than or equal to B; L, MAO-A = B). In the rabbit, the findings with the SCG were similar; the MAO activities of the PB were relatively resistant to both inhibitors; the MAO of the liver required 10(-4) M concentrations of both inhibitors to produce near total inhibition, suggesting that the liver contains an MAO distinct from MAO A and B. All cat tissues examined appeared to contain almost exclusively MAO-B. In this species 5HT, which is generally considered a selective substrate for MAO-A, was oxidized by MAO-B. The findings indicate that criteria for MAO-A, -B, and other subgroups must be defined for each species and tissue.

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