29 novembre 2012 Agora Morris et Rosalind 16 h 45 Accueil 17 h 10 à 17 h 25 Mots de bienvenue • Pierre Moreau, doyen de la Faculté• Brian White-Guay, directeur du BSBP• Marc Perreault, directeur de la Maîtrise en pharmacothérapie avancée 17 h 25 à 19 h 30 Découverte des affiches Curieux de recherche ? Cheminement honor
Comparison of pepck gene expression during reproductive development of chickpea plant (cicer arietinum lJournal of Cell and Molecular Research (2013) 5 (1), 24-34 Molecular docking approach of monoamine oxidase B inhibitors for identifying
new potential drugs: Insights into drug-protein interaction discovery
Department of Biology, Faculty of Science, Shahrekord University, Shahrekord, Iran Received 16 August 2013 Accepted 14 September 2013
Monoamine oxidase (EC, 18.104.22.168) or amine oxidoreductase catalyzes the oxidative deamination of biogenic amines. Abnormal action of the monoamine oxidase B has been associated with neurological dysfunctions including parkinson´s disorder. Monoamine oxidase B inhibitors divulged that these agents were effective in the therapeutic management of Parkinson's disease. Understanding the interaction of monoamine oxidase binding site with inhibitors is crucial for the development of pharmaceutical agents. At the molecular docking, the exact prediction of the binding modes between the inhibitors and protein is of central importance in structure-based drug design. In the current study, we examined two classes of monoamine oxidase B inhibitors. We applied Autodock tools 4.2, in order to set up the docking runs and predict the inhibitors binding free energy. The final product of molecular docking was clustered to specify the binding free energy and optimal docking energy conformation that is investigated as the best docked structure. Docking results indicate that the contribution of van der Waals interactions is greater than electrostatic interactions so that, it can be concluded that all of the inhibitors attached to a hydrophobic binding site in monoamine oxidase B. Among the total of molecules tested, it was proved that 2-(2-cycloheptylidenehydrazinyl)-4-(2,4-dichlorophenyl)-1,3-thiazole has the lowest binding free energy and the lowest Van der Waals energy and also the lowest inhibition constant and subsequently the most experimental affinity. As well as, we find out a possible relationship between the estimated results and experimental data. The selective information from this work is crucial for the rational drug design of more potent and selective monoamine oxidase B inhibitors based on the 8-benzyloxycaffeine scaffold. Keywords: monoamine oxidase B inhibitor, Parkinson´s disorder, molecular docking, binding free energy
and phenylethylamine and is inhibited by deprenyl Monoamine oxidase (EC, 22.214.171.124) or amine Abnormal action of the monoamine oxidase B oxidoreductase is a mitochondrial bound enzyme isoform has been associated with neurological dysfunctions including parkinson´s disorder and monoamine oxidase catalyzes the oxidative alzheimer´s disorder whereas the monoamine oxidase A isoform seems to be associated with exogenous amines, dietary amines, hormones, psychiatric considerations including depression and dopamine, serotonin and neurotransmitters cardiac cellular degeneration . Furthermore, reports have described that the . Therefore, monoamine oxidases are virtually level of monoamine oxidase B in human beings associated with higher brain functions. Two raises four to five fold throughout aging and results isoforms of monoamine oxidases have been in an increase in catalytic reaction products such as described, i.e. monoamine oxidase A and hydrogenperoxide and a decrease in certain monoamine oxidase B. Before their molecular neurotransmitter levels characterization, the differences between these two . Monoamine oxidase isoforms were determined on the basis of substrate B inhibitors, such as D-deprenyl (selegiline) and inhibitor sensitiveness. Monoamine oxidase A divulged that these agents were effective in the therapeutic management of Parkinson's disease. norephinephrine and serotonin and is inhibited by The rationale utilization of monoamine oxidase B inhibitors in parkinson's disorder is based on the selectively catalyzes the oxidation of benzylamine monoamine oxidase B. Inhibition of monoamine Corresponding author E-mail: oxidase B about an increases the dopamine, and [email protected] low levels of dopamine is associated with Molecular docking approach of monoamine oxidase B … parkinson´s disease. Age related additions in heavily based on or influenced by structure-based drug design and screening strategies. neuroprotective impressions of its inhibitors, have In the present work, our purpose was to been studied as rational bases to apply monoamine distinguish correct poses of inhibitor in the binding oxidase B inhibitors in alzheimer's disorder pocket of monoamine oxidase B and to predict the affinity between the inhibitor and monoamine . Regrettably, the usage of monoamine oxidase B. In other words, in this study docking oxidase inhibitors might be confined, although they procedure describes a process by which two are often last line treatment, in some cases, by molecules fit together in three-dimensional adverse effects such as those related to the co- space . At the molecular administration of certain diets or drugs, which can docking, the exact prediction of the binding modes lead to serious hypertensive and hyperpyretic crises between the inhibitors and protein is of central . Hence, tremendous importance in structure-based drug design attempts have been undertaken to discover new pharmaceutical agent that are linked to monoamine Ligand structure
monoamine oxidase B inhibitors is a great interest Due to the special characteristics of monoamine in drug discovery . oxidase, the researchers have focused on various Materials and Methods
Understanding the interactions of monoamine oxidase binding site with inhibitors are crucial for . Since, some of these were the effective inhibitors against the monoamine oxidase B it may Computer aided drug design is an applicable be a potential therapeutic agent for parkinson´s method that can study these interactions and disease. Therefore, we select some of the potent describe significant characteristics for monoamine oxidase binding site recognition monoamine oxidase B . In the current study, we docking is widely applied for approximation of bio examine two classes of monoamine oxidase B molecular complex and in order to analyze the inhibitors; these two classes of inhibitors are 2-(2- structure-function processes and the bio molecular cycloheptylidene design. Drug design is the other application of docking. The precise interaction of agents or benzyloxycaffeine analogues). Figure 1 shows the candidate molecules with their targets is crucial in structure of inhibitors A1-A6 and figure 2 shows the developmental procedure. Docking is applied to the structure of inhibitors B1-B5. predict the binding orientation of small molecular In the present study, molecular modeling of the drug candidates to protein targets, subsequently inhibitors was carried out using Hyperchem 7 predicting the affinity and activity of the drug software. Hyperchem 7 was employed to draw and optimize the structure of inhibitors . In addition, docking is often For all initial structures geometric optimization applied to predict binding affinities of drug calculations by use of molecular mechanics were candidates in virtual screening experiments and in performed and afterward the lowest energy structure-activity conformers were optimized using the semiempirical prioritize synthesis of new drugs . PM3 method, the conjugate gradient and steepest Docking of the small molecules into the structures descent algorithm. At the end these structures of macromolecular targets and scoring their converted to .pdb format by Hyperchem 7 software. potential complementarity to binding site is widely Optimized inhibitor structure was used as input file applied in hit recognition new drugs. Indeed, there are a number of drugs whose development was
Journal of Cell and Molecular Research
Figure 1. Structure of inhibitors A1-A6. [A1] 2-(2-cycloheptylidenehydrazinyl)-4-phenyl-1,3-thiazole, [A2] 2-(2-
Figure 2. Structure of inhibitors B1-B5. [B1] 2-[(2E)-2-(2-methylcyclohexylidene)hydrazinyl]-4-(4-nitrophenyl)-1,3-
resolution was received from the Protein Data Bank In the current study, the protein X-ray crystal and was used as the receptor starting structure. This structure of human monoamine oxidase B with structure comprised a dimeric form of the human 1OJA code and X-ray diffraction at 1.70 Å monoamine oxidase B, with each chain interacting Molecular docking approach of monoamine oxidase B … combined with a local search) with population size codenamed ISN (isatin or indol-2,3-dione) and of 150. Monoamine oxidase B kept rigid in docking several water molecules. Figure 3 shows the x-ray process. The inhibitor structures were attributed crystal structure of monoamine oxidase B in flexible. In other words all the inhibitors rotatable complex with inhibitor ISN and FAD. For docking bonds were adjusted in fewest atoms; note also that process, only the coordinates of chain A and FAD cyclic rotatable bonds are excluded. The other were considered as the receptor structure, and the co-crystallized inhibitor was removed for the parameters, except for the step size parameters that docking studies. The presence of cofactors revealed were chosen to be 0.2 (translation) and 5.0 degrees to be essential for the definition of the docking site. (quaternion and torsion). Finally, by setting all the We applied Autodock tools 4.2, in order to set up parameters, inhibitors were docked to the the docking runs and predict the inhibitors binding monoamine oxidase B Docking protocol
AutoDockTools contain a number of methods for In the current study, AutoDockTools 4.2 was considering the results of docking simulations, applied for docking process. AutoDockTools 4.2 uses a grid-based approach in order to allow exploring of the large conformational space conformations, visualizing interactions between available to drug candidate around an embedded ligands and proteins. At the end of a docking protein in a grid, as well as to provide rapid process, AutoDock writes the data on clustering evaluation of the binding energy of drug candidate and binding energies to the log file. The docking conformations. A probe atom is consecutively results were clustered with 2 Å root mean square located at each grid point, the interaction energy deviation and were ranked according to the between the probe and the target protein is estimated binding free energy. The structure with estimated, and the value is stored in the grid. This proportional lower binding free energy and the grid of energies may then be applied as a lookup most conformation in cluster was selected for the table during the docking simulation optimum docking conformation . .
The intensity of the interaction between the AutoDockTools 4.2 was employed to docking inhibitor and the receptor can be evaluated process of inhibitors to monoamine oxidase B experimentally and is often described as the . Initially, all of the polar dissociation constant, Kd, or by the concentration hydrogens were added to the inhibitors and of inhibitor that inhibits activity by 50%, the IC50. Gasteiger-Marsili atomic partial charges were set The binding free energy is the thermodynamic for them, and all the inhibitors rotatable bonds were quantity that is determined by equation 1 and is of adjusted in fewest atoms. The final inhibitor interest in computational structure-based design structures were saved in .pdbqt format. Then polar hydrogen was added to the protein crystal structure and the kollman atomic partial charge was set for Equation 1
monoamine oxidase B. The final protein structure was saved in .pdbqt format. An extended pdb format, called pdbqt, is applied for coordinate files, The relationship between the binding free energy which include atomic partial charges and atom ∆G and the experimentally determined Kd or IC50 types; pdbqt files as well include data on the is demonstrated in equation 2. torsional degrees of freedom . Grid box was created by Autogrid 4 with 30 × 30 × Equation 2
30 Å in x, y and z directions with 0.375 Å spacing and center of box was located on the active site The interactions between the inhibitor and the according to co-crystallized inhibitor coordination. receptor also can be measured by means of The monoamine oxidase B active site was easily AutoDock 4.2. In the present work, our purpose distinguished as the hydrophobic cavity comprising was to attain an agreement between the docking the co-crystallized ligand ISN. The genetic results and experimental data. algorithm was used to determine the probable The AutoDock 4.2 force field is designed to accommodate for each inhibitor to monoamine estimate the binding free energy of inhibitors to protein. It includes an updated charge-based Lamarckian genetic algorithm (Genetic Algorithm Journal of Cell and Molecular Research desolvation term, advances in the directionality of 11.54 kcal/mol). The more negative is the free hydrogen bonds, and various improved models of binding energy, the more potent is the interaction. the unbound state. AutoDock 4.2 applies a semi- According to the table 1, among the total of empirical free energy force field and grid-based molecules tested, it was proved that A3 has the docking to assess conformations during docking lowest binding free energy (-11.96 kcal/mol), Van process. Equation 3 represent the docking binding der Waals energy (-13.14 kcal/mol) and also the free energy, this formula automatically was lowest inhibition constant (1.70 n M) and computed by AutoDock 4.2 . subsequently the most experimental affinity. It was proved that after A3, B3 also has the lowest binding Equation 3
free energy (-11.54 kcal/mol), the lowest Van der Waals energy (-12.69 kcal/mol), the lowest inhibition constant (3.50 n M) and the most In the above formula, the final intermolecular experimental affinity. In other words, A3 and B3 energy is calculated with equation 4, so that the have the highest interactions and the more potential final intermolecular energy involves in van der binding affinity for the enzyme binding site. Special attention has been devoted to the electrostatic contribution between the inhibitor and substituent at thiazole ring. 2,4-dichlorophenyl the protein binding site. substitution leads to the highest potential binding affinity at 2-(2-cycloheptylidenehydrazinyl) and Equation 4
methyl cyclohexylidene hydrazinyl derivatives. It has been found clearly that, in the presence of a dichlorophenyl substituent in the 2,4 position, the potency of inhibitor was increased. The active site is frequently known from crystal Molecular docking was applied to describe and distinguishing of active sites can play a central role find out the binding sites in monoamine oxidase B. in realizing protein function . The final product of molecular docking, as the best The docking results indicate that all inhibitors docked structure was clustered to specify the bind to monoamine oxidase B active site; active site binding free energy and optimal docking energy is a hydrophobic pocket that was surrounded by the conformation. As well as we consider the molecular aromatic and aliphatic residues. The active site of docking results to elucidate their binding mode in monoamine oxidase B constitutes of an entrance the monoamine oxidase B. cavity and substrate cavity; depending on the nature Table 1 summarizes the docking results. In this of the ligand, two cavities can be separated or study the inhibition constant (Ki) and the RMSD value for drug-like molecules were also determined. Negative values of predicted free energies of In structure-based design, the known or predicted binding show that all inhibitors correctly docked to shape of the binding site is used to optimize the the crystal structure of the monoamine oxidase B. inhibitor as a best fit to the receptor. As well as, the Docking results also indicate that the contribution orientations of these inhibitors in the active site are of van der Waals interactions is greater than very important, with their Ki values, for rational electrostatic interactions so that, it can be drug design. In most of the cases, careful concluded that all of the inhibitors attached to a observations of the figures divulge that inhibitor hydrophobic binding site in monoamine oxidase B. positioning in the active site sits reasonably well. In other words, the non-polar interactions between The binding manners and geometrical orientation of monoamine oxidase B and inhibitors are the main all compounds in the binding site were nearly factor in the connectivity features and they are the identical, hence proposing that all the inhibitors dominant component contributing to the binding have the same interactions with enzyme and affinity. Among the molecules tested of A class, A3 occupied a common space in the receptor. Hydrophobic cavity of binding site constitutes the inner cavity of the active site, and comprises the lowest binding free energy (-11.96 kcal/mol). As residues such as Tyr 60, Leu171, Ile198, Gln206, well as, among the molecules tested of B class, B3 Tyr326, Leu328, Phe343, Tyr398, Tyr435. Fig 4 shows the lowest energy configuration of A3- monoamine oxidase B complex. Observations of demonstrated the lowest binding free energy (- the docked conformation of A3 demonstrated
Molecular docking approach of monoamine oxidase B … interactions with many residues; in this complex, interactions. Fig 6-A shows the best virtual docking A3 was located inside the cavity that comprising pose of A3 and the superimposition of A3 and ISN, the residues such as Gly57, Gly58, Leu171, Ile198, and Fig 6-B shows the best virtual docking pose of Gln206, Tyr326, Phe343, Tyr398, Thr426, Gly434, B3 and the superimposition of B3 and ISN. In this Tyr435, Met436. And Fig 5 shows the lowest docked conformation, the A3 and B3 interact with energy configuration of B3-monoamine oxidase B flavin moiety of the FAD via a hydrogen bond and complex, B3 was located inside the cavity that show tight interactions with Gln206, Tyr326, containing the residues such as Gly57, Gly58, Phe343, Tyr398 and Tyr435 (Fig 6 A-B). For Tyr60, Leu171, Gln206, Tyr326, Phe343, Tyr398, superimposition of A3 and B3 with ISN, the indol Thr426, Gly434, Tyr435, Met436. ring is located between Tyr435 and Tyr398 in the Other interactions proposed by the docking hydrophobic cavity with an upright conformation to consequences were the hydrophobic interactions of flavin ring of FAD. Therefore, AutoDock 4.0 the inhibitors hydrophobic groups, as they were viewed as reliable for docking A3 and B3, and observed oriented towards the co-crystallized related compounds into monoamine oxidase B. ligand ISN, so that they have similar hydrophobic Figure 3. X-ray crystal structure of monoamine oxidase B in complex with inhibitor ISN (purple) and FAD (red).
Table 1. Autodock's binding free energy derived from the docking studies on monoamine oxidase B.
Abbreviations: ∆Gbinding, Estimated Free Energy of Binding (kcal/mol); ΔGvdw, vander Waals or Lennard–Jones potential factor of binding free energy (kcal/mol); ΔGelec, electrostatic factor of binding free energy (kcal/mol); ΔGinter, Gibbs free energy of binding (kcal/mol); ΔGtors, torsional energy of binding (kcal/mol); ∆Gunbound, unbound System's energy (kcal/mol); Ki, inhibition constant (nM); RMSD, reference root mean square deviation ; IC50 refers to the experimental predicted activity (mM). Refrence of inhibitor.
Journal of Cell and Molecular Research
Figure 4. Docking result of A3 (magenta) with monoamine oxidase B. The lowest energy configuration of A3-
monoamine oxidase B complex is demonstrated in VMD(A) and Ligplot (B) presentations. In Ligplot presentations (B),
carbons are in black, nitrogens in blue and oxygens in red.
Molecular docking approach of monoamine oxidase B …
Figure 5. Docking result of B3 (orange) with monoamine oxidase B. The lowest energy configuration of B3-
monoamine oxidase B complex is demonstrated in VMD(A) and Ligplot (B) presentations. In Ligplot presentations (B),
carbons are in black, nitrogens in blue and oxygens in red.
Journal of Cell and Molecular Research
Figure 6. Best virtual docking pose of A3 and B3. (A), superimposition of A3 (magenta) and FAD (red) and ISN
(purple); (B) superimposition of B3 (orange) and FAD (red) and ISN (purple).
Molecular docking approach of monoamine oxidase B … Discussion
The target of this study was to carry out 1- Bortolato M., Chen K. and Shih J. C. (2008) molecular docking to estimate the binding free Monoamine oxidase inactivation: from pathophysiology energies and inhibition constants of tested to therapeutics. Advanced drug delivery reviews monoamine oxidase B inhibitors and to compare 60:1527-1533. 2- Brooijmans N. 2009. Docking methods, ligand design these computational results with those of the and validating data sets in the structural genomics era. In experimentally obtained results. Structural Bioinformatics. J.G.a.P.E. Bourne, editor. In the resent study, we employed computational John Wiley & Sons. approaches, such as molecular docking to estimate 3- Carroll R. T., Dluzen D. E., Stinnett H., Awale P. S., the binding free energy of two classes of Funk M. O. and Geldenhuys W. J. (2011) Structure- monoamine oxidase B inhibitors. Compare with the van der Waals and electrostatic energies for these thiazolidinedione-type compounds with monoamine components showed a significant share of the van oxidase B. Bioorganic & medicinal chemistry letters der Waals energies. Our results clearly showed that non polar interactions play a significant role in 4- Chimenti F., Maccioni E., Secci D., Bolasco A., Chimenti P., Granese A., Befani O., Turini P., Alcaro S. determining the binding free energy. Our findings and Ortuso F. (2005) Synthesis, molecular modeling studies, and selective inhibitory activity against might demonstrate a crucial scaffold for the monoamine oxidase of 1-thiocarbamoyl-3, 5-diaryl-4, 5- development of monoamine oxidase inhibitors. All dihydro-(1 H)-pyrazole derivatives. Journal of medicinal inhibitors bind to monoamine oxidase B active site chemistry 48:7113-7122. and subsequently inhibit it. So that they have potent 5- Chimenti F., Secci D., Bolasco A., Chimenti P., affinity to the monoamine oxidase B and thus they Bizzarri B., Granese A., Carradori S., Yanez M., Orallo can behave like as the pharmaceutical agents. F. and Ortuso F. (2009) Synthesis, Molecular Modeling, Among the tested derivatives we preferred A3 and and Selective Inhibitory Activity against Human B3 as potent anti monoamine oxidase B agents. Monoamine Oxidases of 3-Carboxamido-7-Substituted Coumarinsâ€ Journal of medicinal chemistry 52:1935- Understanding, an atomic-level of the catalytic and inhibition mechanisms of monoamine oxidase B 6- Chimenti F., Secci D., Bolasco A., Chimenti P., could assist to search for rationally-designed Granese A., Befani O., Turini P., Alcaro S. and Ortuso F. inhibitors of monoamine oxidase B, and would be (2004) Inhibition of monoamine oxidases by coumarin- of significant importance monoamine oxidase B 3-acyl derivatives: biological activity and computational activity. In the present work, our purpose was to study. Bioorganic & medicinal chemistry letters attain an agreement between the docking results and experimental data. We discovered good 7- Chimenti F., Secci D., Bolasco A., Chimenti P., relationship between the estimated results and Granese A., Carradori S., Befani O., Turini P., Alcaro S. experimental data. The selective information from and Ortuso F. (2006) Synthesis, molecular modeling studies, and selective inhibitory activity against this work is crucial for the rational drug design of monoamine oxidase of N-bis [2-oxo-2-H-benzopyran]-3- more potent and selective monoamine oxidase B carboxamides. Bioorganic & medicinal chemistry letters inhibitors based on the 8-benzyloxycaffeine scaffold. Such observations can also help to study 8- Coelho Cerqueira E., Netz P. A., Diniz C., Petry do 8-benzyloxycaffeine, by increased metabolism of Canto V. and Follmer C. (2010) Molecular insights into biogenic amines within some key areas of the human monoamine oxidase (MAO) inhibition by 1, 4- central nervous system, as an effective scaffold for naphthoquinone: Evidences for menadione (vitamin K3) rational design of novel and potential drugs against acting as a competitive and reversible inhibitor of MAO. diseases precipitated. Bioorganic & medicinal chemistry 19:7416-7424. 9- Delogu G., Picciau C., Ferino G., Quezada E., Podda G., Uriarte E. and Vina D. (2011) Synthesis, human Note: All the figures are color in online version.
monoamine oxidase inhibitory activity and molecular docking studies of 3-heteroarylcoumarin derivatives. European journal of medicinal chemistry 46:1147-1152. 10- Froimowitz M. (1993) HyperChem: a software I thank to the Golestan University for their package for computational chemistry and molecular financial support to perform this work. modeling. BioTechniques 14:1010-1013. 11- Geldenhuys W. J., Funk M. O., Van der Schyf C. J. and Carroll R. T. (2012) A scaffold hopping approach to identify novel monoamine oxidase B inhibitors. Bioorganic & medicinal chemistry letters 22:1380-1383. Journal of Cell and Molecular Research 12- Goodsell D. S. (2009) Computational docking of 26- Scheer M., Grote A., Chang A., Schomburg I., biomolecular complexes with AutoDock. Cold Spring Munaretto C., Rother M., Sohngen C., Stelzer M., Thiele Harbor protocols 2009:pdb prot5200. J. and Schomburg D. (2011) BRENDA, the enzyme 13- Harkcom W. T. and Bevan D. R. (2007) Molecular information system in 2011. Nucleic acids research docking of inhibitors into monoamine oxidase B. Biochemical and biophysical research communications 27- Strydom B., Malan S. F., Castagnoli N., Bergh J. J. and Petzer J. P. (2010) Inhibition of monoamine oxidase 14- Herraiz T. and Chaparro C. (2005) Human by 8-benzyloxycaffeine analogues. Bioorganic & monoamine oxidase is inhibited by tobacco smoke: b- medicinal chemistry 18:1018-1028. carboline alkaloids act as potent and reversible 28- Taylor R. D., Jewsbury P. J. and Essex J. W. (2002) inhibitors. Biochemical and Biophysical Research A review of protein-small molecule docking methods. Communications 326:378–386. Journal of Computer-Aided Molecular Design 16:151– 15- Ivanciuc O. (1996) HyperChem Release 7 for Windows. Journal of chemical information and computer 29- Van der Walt E. M., Milczek E. M., Malan S. F., sciences 36:612-614. Edmondson D. E., Castagnoli Jr N., Bergh J. J. and 16- Jensen S. B., Olsen A. K., Pedersen K. and Petzer J. P. (2009) Inhibition of monoamine oxidase by ( Cumming P. (2006) Effect of monoamine oxidase E)-styrylisatin analogues. Bioorganic & medicinal inhibition on amphetamine evoked changes in dopamine chemistry letters 19:2509-2513. receptor availability in the living pig: A dual tracer PET 30- Wu G., Robertson D. H., Brooks C. L. and Vieth M. study with [11C] harmine and [11C] raclopride. Synapse (2003) Detailed analysis of gridbased molecular docking: A case study of C-DOCKER. A CHARM 17- Kitchen D. B., Decornez H. l. n., Furr J. R. and based MD docking algorithm. Journal of computational Bajorath J. r. (2004) Docking and scoring in virtual chemistry 24:1549-1562. screening for drug discovery: methods and applications. Nature reviews Drug discovery 3:935-949. 18- Lewis A., Miller J. H. and Lea R. A. (2007) Neurotoxicology 28:182-195. 19- Luhr S., Vilches-Herrera M., Fierro A., Ramsay R. R., Edmondson D. E., Reyes-Parada M., Cassels B. K. and Iturriaga-Vasquez P. (2010) 2-Arylthiomorpholine derivatives as potent and selective monoamine oxidase B inhibitors. Bioorganic & medicinal chemistry 18:1388- 20- Morris G. M., Huey R., Lindstrom W., Sanner M. F., Belew R. K., Goodsell D. S. and Olson A. J. (2009) AutoDock4 and AutoDockTools4: Automated docking computational chemistry 30:2785-2791. 21- Morris G. M., Huey R. and Olson A. J. (2008) Using AutoDock for ligand-receptor docking. Current protocols in bioinformatics / editoral board, Andreas D. Baxevanis . [et al.] Chapter 8:Unit 8 14. 22- Mu L.-H., Wang B., Ren H.-Y., Liu P., Guo D.-H., Wang F.-M., Bai L. and Guo Y.-S. (2012) Synthesis and inhibitory effect of piperine derivates on monoamine oxidase. Bioorganic & medicinal chemistry letters. 23- Nagatsu T. (2004) Progress in monoamine oxidase (MAO) research in relation to genetic engineering. Neurotoxicology 25:11-20. 24- Oreland L. (2004) Platelet monoamine oxidase, personality and alcoholism: the rise, fall and resurrection. Neurotoxicology 25:79-89. 25- Reniers J., Meinguet C., Moineaux L., Masereel B., Vincent S. P., Frederick R. and Wouters J. (2011) Synthesis and inhibition study of monoamine oxidase, indoleamine 2, 3-dioxygenase and tryptophan 2, 3- dioxygenase by 3, 8-substituted 5 H-indeno [1, 2 c] pyridazin-5-one derivatives. European journal of medicinal chemistry 46:6104-6111.
bei Erwachsenen Anleitung zur medikamentösen Tumorschmerztherapie (Überarbeitet von Dr. Beekhchand Permar) Pflegeinterventionen in der Schmerztherapie Herausgeber: Arbeitsgruppe Schmerztherapie im Onkologischen Zentrum Westpfalz für die Arbeitsgruppe: Prof. Dr. Ch. Madler, Anästhesiologie Prof. Dr. H. Link, Medizinische Klinik