Recognition dynamics of dopamine to human Monoamine oxidase B: role of Leu171/Gln206 and conserved water molecules in the active site cavity

Dasgupta, Subrata; Mukherjee, Somenath; Mukhopadhyay, Bishnu P.; Banerjee, Avik; Mishra, Deepakkumar

doi:10.1080/07391102.2017.1325405

Cited by 18 publications

(13 citation statements)

References 57 publications

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“…The overall characteristics of the interactions of virodhamine with human MAO-B are similar to those of kynuramine (Fig. 9), the non-selective MAO-A/B substrate employed in these studies, and also to those reported recently for dopamine, the selective MAO-B substrate [53]. …”

Section: Discussionsupporting

confidence: 76%

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B

Pandey

Chaurasiya

Tekwani

et al. 2018

Biochemical Pharmacology

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The endocannabinoid system plays an important role in the pathophysiology of various neurological disorders, such as anxiety, depression, neurodegenerative diseases, and schizophrenia; however, little information is available on the coupling of the endocannabinoid system with the monoaminergic systems in the brain. In the present study, we tested four endocannabinoids and two anandamide analogs for inhibition of recombinant human MAO-A and -B (monoamine oxidase). Virodhamine inhibited both MAO-A and -B (IC values of 38.70 and 0.71 μM, respectively) with ∼55-fold greater inhibition of MAO-B. Two other endocannabinoids (noladin ether and anandamide) also showed good inhibition of MAO-B with IC values of 18.18 and 39.98 μM, respectively. Virodhamine was further evaluated for kinetic characteristics and mechanism of inhibition of human MAO-B. Virodhamine inhibited MAO-B (K value of 0.258 ± 0.037 μM) through a mixed mechanism/irreversible binding and showed a time-dependent irreversible mechanism. Treatment of Neuroscreen-1 (NS-1) cells with virodhamine produced significant inhibition of MAO activity. This observation confirms potential uptake of virodhamine by neuronal cells. A molecular modeling study of virodhamine with MAO-B and its cofactor flavin adenine dinucleotide (FAD) predicted virodhamine's terminal -NH group to be positioned near the N5 position of FAD, but for docking to MAO-A, virodhamine's terminal -NH group was far away (∼6.52 Å) from the N5 position of FAD, and encountered bad contacts with nearby water molecules. This difference could explain virodhamine's higher potency and preference for MAO-B. The binding free energies for the computationally-predicted poses also showed that virodhamine was selective for MAO-B. These findings suggest potential therapeutic applications of virodhamine for the treatment of neurological disorders.

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Section: Discussionsupporting

confidence: 76%

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B

Pandey

Chaurasiya

Tekwani

et al. 2018

Biochemical Pharmacology

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“…Proteins can contain evolutionarily conserved networks of coordinated "water" molecules, many bindingn ear or directly to metal ions. [66][67][68][69][70][71][72][73][74][75][76] The protonation state of such water molecules cannot be determined from X-ray crystallography,a nd these "water" molecules might actually be hydroxide, rather than water. [77] In the case of SOD1, for example, there is ac onserved water bound to its active site Cu 2 + ,a nd three additional water molecules bound within 4.0 from the buried binuclear active site.…”

Section: Introductionmentioning

confidence: 99%

What Are We Missing by Not Measuring the Net Charge of Proteins?

Zahler

Shaw

2019

Chemistry A European J

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The net electrostatic charge (Z) of a folded protein in solution represents a bird's eye view of its surface potentials—including contributions from tightly bound metal, solvent, buffer, and cosolvent ions—and remains one of its most enigmatic properties. Few tools are available to the average biochemist to rapidly and accurately measure Z at pH≠pI. Tools that have been developed more recently seem to go unnoticed. Most scientists are content with this void and estimate the net charge of a protein from its amino acid sequence, using textbook values of pKa. Thus, Z remains unmeasured for nearly all folded proteins at pH≠pI. When marveling at all that has been learned from accurately measuring the other fundamental property of a protein—its mass—one wonders: what are we missing by not measuring the net charge of folded, solvated proteins? A few big questions immediately emerge in bioinorganic chemistry. When a single electron is transferred to a metalloprotein, does the net charge of the protein change by approximately one elementary unit of charge or does charge regulation dominate, that is, do the pKa values of most ionizable residues (or just a few residues) adjust in response to (or in concert with) electron transfer? Would the free energy of charge regulation (ΔΔGz) account for most of the outer sphere reorganization energy associated with electron transfer? Or would ΔΔGz contribute more to the redox potential? And what about metal binding itself? When an apo‐metalloprotein, bearing minimal net negative charge (e.g., Z=−2.0) binds one or more metal cations, is the net charge abolished or inverted to positive? Or do metalloproteins regulate net charge when coordinating metal ions? The author's group has recently dusted off a relatively obscure tool—the “protein charge ladder”—and used it to begin to answer these basic questions.

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“…Recently, in 2017, Marsavelski and Vianello applied a combination of MD simulations, molecular mechanics with Poisson–Boltzmann and surface area salvation (MM‐PBSA) binding free energy evaluations, and QM cluster calculations to address the unanticipated, nevertheless intriguing MAO‐B selectivity for N ‐methylhistamine (NMH) above histamine (HIS), differing exclusively in a single methyl group separated in space from the reactive ethylamino center . The study established that the prevailing in vivo MAO‐B selectivity toward the two substrates was extended by the lower activation free energy for NMH, in proximity with more favorable response exergonicity and active‐site binding.…”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

“…Dasgupta et al carried out extensive MD simulation studies of DA docked hMAO‐B structures. The study disclosed the presence of 13 conserved or semiconserved water molecular sites playing a significant role in the recognition of DA (protonated as well as free amine form) to catalytic tyrosine residues, prosthetic group (FAD), and gating residues.…”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

“…Beside the interplay of water molecules, the catalytic aromatic cage was found to be stabilized by π–water, π–C‐H, and π–π interactions. Thus the topology of conserved water molecular sites along with the hydration dynamics of catalytic residues, FAD and DA during the simulation studies have added a new feature on the substrate binding chemistry in hMAO‐B which may be useful for substrate analog inhibitor design …”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

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Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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Recognition dynamics of dopamine to human Monoamine oxidase B: role of Leu171/Gln206 and conserved water molecules in the active site cavity

Cited by 18 publications

References 57 publications

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B

Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and -B

What Are We Missing by Not Measuring the Net Charge of Proteins?

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

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