Computer-aided drug design of broad-spectrum antiviral compounds

202 Pages·2017·7.78 MB·French

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