Computer-aided drug design of broad-spectrum antiviral compounds PDF
Preview Computer-aided drug design of broad-spectrum antiviral compounds
UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES UMR 7140 THÈSE présentée par : Kyrylo KLIMENKO soutenue le: 14 mars 2017 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/Spécialité : Chimie/Chémoinformatique Computer-aided drug design of broad-spectrum antiviral compounds THÈSE dirigée par : M. VARNEK Alexandre Professeur, Université de Strasbourg M. KUZMIN Victor Professeur, Institut de Chimie Physique, Odessa, Ukraine RAPPORTEURS : M. ERTL Peter Docteur, HDR, société Novartis M. TABOUREAU Olivier Professeur, Université Paris Diderot AUTRES MEMBRES DU JURY : Mme. KELLENBERGER Esther Professeur, Université de Strasbourg Mr Kyrylo Klimenko was a member of the European Doctoral College of the University of Strasbourg during the preparation of his PhD thesis (2013-2016), class Dmitri Mendeleev. In addition to his mainstream research topic, he has attended lectures and seminars dedicated to general European policies and values presented by international experts. This PhD research project was carried out in scope of collaboration between the University of Strasbourg, France and A.V. Bogatsky Physico-Chemical Institute, Ukraine. Acknowledgements First of all, I would like to express my gratitude to my academic advisors, Prof Alexandre Varnek and Prof Victor Kuz`min for their brilliant guidance in completing the academic challenges I have faced. I am also thankful to the French Embassy in Ukraine for providing financial means to the project’s completion. I would like to thank all the members of the jury, Prof Olivier Taboureau, Dr Peter Ertl and Prof Esther Kellenberger for accepting to judge and review my work. I would also like to express my gratitude to my senior colleagues Dr. Dragos Horvath, Dr Gilles Marcou, Dr Pavel Polishchuk, as well as, former and current PhD students Dr. Helena Gaspar, Dr. Fiorela Ruggiu, Grace Delouis, Pavel Sidorov, Timur Gimadiev and Julien Denos for their advice and support. I am thankful to my collaborators from Physico-chemical Institute, Ukraine and Institute of Chemical Biology and Fundamental Medicine Russia who provided experimental evidence to my theoretical findings. Special thanks to Dr. Olga Klimchuk and Soumia Hnini for their help on accommodation and administration tasks. I am deeply and forever indebted to my parents and friends for their love and support. ABSTRACT Virtual screening and cartography of chemical space approaches have been used for design of broad-spectrum antivirals acting as nucleic acids intercalators. The 1st part of thesis reports QSPR model for aqueous solubility of organic molecules within the wide temperature range. This model was later used for solubility assessment of antiviral compounds. In the second part of work, structural filters, QSAR and pharmacophore models were developed then used to screen a database containing some 3.2 M compounds. This resulted in 55 hits which were synthesized and experimentally tested. Two lead compounds displayed high activity against Vaccinia virus and low toxicity. In the 3d part of the thesis, Generative Topographic Mapping (GTM) approach was used to build 2D maps of chemical space of antiviral compounds. Experimental data on antiviral compounds were extracted from ChEMBL database, curated and annotated by major virus Genus. Selected dataset was used to build maps on which all other ChEMBL compounds were projected. Analysis of the maps revealed structural motifs characterizing particular types of antivirals. DECLARATION • This is my own work • Information sources were acknowledged and fully referenced. Kyrylo Klimenko March, 2017
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