المؤلفون: Vishalgiri Goswami, Dhaval Patel, Shishir Rohit, Udit Chaube, Bhumika Patel

المصدر: Results in Chemistry, Vol 7, Iss , Pp 101482- (2024)

مصطلحات موضوعية: Porcupine, Homology modelling, Wnt signaling, Ramachandran plot, LGK-974, Molsoft ICM Pro, Chemistry, QD1-999

الوصف: Wnt signaling is a critical pathway involved in cell proliferation, differentiation and cellular homeostasis. To address treatment need of diseases associated with the dysregulated Wnt signaling like cancer, Alzheimer’s disease, Osteoporosis, Myocardial infarction etc.; small molecules that target the very first and unique component of the Wnt pathway, Porcupine enzyme, have been proven to be effective. Till date, none of the Porcupine inhibitor has reached to market. To design the novel Porcupine inhibitors, there was a need of crystal structure of Porcupine but in 2019, it was not resolved and deposited in the protein data bank. So, with an aim to predict its 3D structure, homology modeling study was performed using two distinct platforms; I-TASSER and Molsoft ICMPro so that we could use the best validated model for the designing of NCEs. Both the generated homology models were compared through Ramachandran plot, Protein health tool of Molsoft ICM and other tools available on metaserver, SAVES v6.0. Molsoft model was found better with 84.6 % residues in most favored region and only 0.3 % residues in disallowed region in Ramachandran plot in comparison to 75.9 % and 1.7 % residues respectively in I-TASSER model. The ICM model was further refined for 50 ns under MD simulation where it got stabilized after 36 ns. Quantification of protein was done by Radius of Gyration (ROG) where model showed larger ROG value of 23.25°A which indicated closely packed structure. Binding site in the predicted structure of Porcupine was identified using ICM binding pocket identifier and used for molecular docking of known Porcupine inhibitors like IWP-2, IWP-3, IWP-L6, and LKG974. Key binding site residues; Arg124, Phe257, Leu261, Val302, Trp305, Asn306, Ser310, Leu313, His341, Phen345, Ala349, Val350 etc. involved in the interaction were identified after MD simulation which can be useful in designing of novel porcupine inhibitors in future.

وصف الملف: electronic resource

Relation: http://www.sciencedirect.com/science/article/pii/S2211715624001784; https://doaj.org/toc/2211-7156

URL الوصول: https://doaj.org/article/394ebf730598485fa2f11d8c9f7b5045

المؤلفون: Aakash Patel, Hala Guedouari, Elzbieta Janda, Karine Reybier, Istvan Gacsalyi, Vishalgiri Goswami, Jean A. Boutin, Adeline Giganti, Mathias Antoine, Monivan Chhour, Marie-Claude Viaud-Massuard, Hervé Da Costa, Marc Bertrand, Pierre Ducrot, Jérôme Paysant, Patrick P. Michel, Gilles Ferry, Thierry Le Diguarher, Daniel A. Kane, Françoise Nepveu, Frédéric Bouillaud, Karen Brebner, Gérald Guillaumet, Etienne C. Hirsch, Philippe Dupuis, Johann Stojko

المساهمون: Institut de Recherches SERVIER (IRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Università degli Studi 'Magna Graecia' di Catanzaro [Catanzaro, Italie] (UMG), Egis Pharmaceuticals, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), St. Francis Xavier University (StFX), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Eurofins-Cerep, Technologie Servier, GICC UMR 7292 CNRS, IMT (Innovation moléculaire et thérapeutique) (IMT), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Oxygen Healthcare Pvt Ltd, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli Studi 'Magna Graecia' di Catanzaro = University of Catanzaro (UMG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), GICC EA 7501, IMT (Innovation moléculaire et thérapeutique) (IMT), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Hirsch, Etienne, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

المصدر: Molecular Pharmacology
Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2019, 95 (3), pp.269-285. ⟨10.1124/mol.118.114231⟩
Molecular Pharmacology, 2019, 95 (3), pp.269-285. ⟨10.1124/mol.118.114231⟩

مصطلحات موضوعية: 0301 basic medicine, Male, Rats Wistar, Pyridines, [SDV]Life Sciences [q-bio], Quinone Reductases / antagonists & inhibitors, Reductase, Cell Membrane / drug effects, 03 medical and health sciences, Mice, 0302 clinical medicine, Pyrrolizidine Alkaloids / pharmacology, In vivo, Cell Line, Tumor, NAD(P)H Dehydrogenase (Quinone), [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Quinone Reductases, Rats, Wistar, NAD(P)H Dehydrogenase (Quinone) / metabolism, Pyrrolizidine Alkaloids, Pharmacology, chemistry.chemical_classification, Reactive oxygen species, Chemistry, Cell Membrane, Autophagy, Neurodegeneration, Reactive Oxygen Species / metabolism, Hep G2 Cells, Cell Membrane / metabolism, medicine.disease, Quinone, Cell Line / Tumor, Rats, [SDV] Life Sciences [q-bio], 030104 developmental biology, Enzyme, Biochemistry, Molecular Medicine, NAD+ kinase, Reactive Oxygen Species, 030217 neurology & neurosurgery, Pyridines / pharmacology

الوصف: International audience; Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC50 = 5-16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.

وصف الملف: application/pdf

URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c332ae7dd4579c5014783569d4574301
https://www.hal.inserm.fr/inserm-02334766