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Characterization of Natural Product Biological Imprints for Computer-Aided Drug Design Applications Noe Sturm

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Characterization of natural product biological imprints for computer-aided drug design applications Noe Sturm To cite this version: Noe Sturm. Characterization of natural product biological imprints for computer-aided drug design applications. Cheminformatics. Université de Strasbourg, 2015. English. NNT : 2015STRAF059. tel-01300872 HAL Id: tel-01300872 https://tel.archives-ouvertes.fr/tel-01300872 Submitted on 11 Apr 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES Laboratoire d’Innovation Thérapeutique, UMR 7200 en cotutelle avec Eskitis Institute for Drug Discovery, Griffith University THÈSE présentée par Noé STURM soutenue le : 8 Décembre 2015 pour obtenir le grade de : Docteur de l’université de Strasbourg Discipline/Spécialité : Chimie/Chémoinformatique Caractérisation de l’empreinte biologique des produits naturels pour des applications de conception rationnelle de médicament assistée par ordinateur THÈSE dirigée par : KELLENBERGER Esther Professeur, Université de Strasbourg QUINN Ronald Professeur, Université de Griffith, Brisbane, Australie RAPPORTEURS : IORGA Bogdan Chargé de recherche HDR, Institut de Chimie des Substances Naturelles, Gif-sur-Yvette GÜNTHER Stefan Professeur, Université Albert Ludwigs, Fribourg, Allemagne Acknowledgments First of all, I would like to thank my two supervisors Professor Kellenberger Esther and Professor Quinn Ronald for their excellent assistance, both academic and personal in nature. Esther, I remember that day, as I was still an undergraduate student. Next to a coffee achie you asked the ope uestio: who’s keen for Australia?! As simple as it sounds, this question changed my life. Since then, you have shaped me, just like biosynthetic enzymes shape natural products and I sense that I will retain this imprint! Now, my candidature has come to an end, it’s tie to prove what I leared. I will remember this important period of my life with much nostalgia but I am also looking forward to the future. Really, I would like to express all my gratitude to you for your precious help, your opportunism and also for your patience (I know you would have needed this with me!). I owe you more than my PhD project. Also, I would like to extend my gratitude to Professor Quinn without whom none of this could have happen. I really enjoyed being part of the Eskitis family. I learned a lot! I particularly enjoyed each of your intervention during group meetings. I’d like to thank you because you gave me the opportunity to study natural products and their biosynthetic origins. It is fascinating. I also would like to express my admiration to you for what you do. I ea, who would’t wat to have such an incredible driving power. I also would like to thank Dr. Rognan Didier who has allowed me to work in his laboratory in the first place. Your gifted nature for science impresses me even today. It was an honor to work with your lab. III I would also like to thank Dr. Campitelli who was an excellent colleague at Eskitis University. Also, as part of Eskitis engineering members, I would like to thanks Stephen Toms for his sympathy and devotion to the group. Then, I would like to thank my PhD colleagues. I’ll start with a special thanks to Jeremy Desaphy and Jamel Meslamani. You guys are awesome! Both of you have guided my first steps. I also would like to thank other colleagues in Illkrich, Guillaume Bret, Franck Da Silva, Ina Slynko and the ones that I am forgetting for their supportive behaviors. At Eskitis, there are numerous past and present PhD colleagues that were just great with me. I have special thoughts to Liliana Pedro and her devotion to science. Thanks to the French connection, Marie-Laure Vial, Roai Morvel Lepage and Fanny Lombard for your efforts in creating social events at Eskitis. Benoît Serive (désolé de te mettre dans le lot des doctorants), Asmaa Boufridi (you are one of us) and Jan Lanz (a swiss is everything), I am glad you came at Eskitis. And last but not least thanks to Shaz for all the chicken drawings he left on my desk. I would like to express a special thanks to Pauline Fabre for her very supportive and attentive behavior regarding me in all aspects of life. If I am here today, it is also thanks to you. Last, I would like to thanks the members of my family, for their support during my candidature. It was always hard to leave France mainly because of you. IV Résumé La comparaison de site peut-elle vrifier l’hypothse: «Les origines biosynthétiques des produits naturels leurs confèrent des activités biologiques»? Pour répondre à cette question, nous avons développé un outil modélisant les propriétés accessibles au solvant des sites de liaison. La méthode a montré des aspects intéressants, mais elle souffre d’ue sesiilit au coordonnées atomiques. Cependant, des méthodes eistates ous ot peris de prouver ue l’hypothse est valide pour la faille des flavooïdes. Afi d’tedre l’tude, ous avos dvelopp u procd autoatiue capale de rechercher des structures d’ezyes de biosynthèse de produits naturels disposant de sites actifs capables de lier une molécule de petite taille. Nous avons trouvé les structures de 117 enzymes. Les structures nous ont permis de caractériser divers modes de liaison substrat-enzyme, nous indiquant que l’epreite iologiue des produits aturels ne correspond pas toujours au modèle « clé-serrure ». V Abstract Can computational binding site similarity tools verify the hypothesis: Biosynthetic moldings give potent biological activities to natural products? To answer this question, we designed a tool modeling binding site properties according to solvent exposure. The method showed interesting characteristics but suffers from sensitivity to atomic coordinates. However, existing methods have delivered evidence that the hypothesis was valid for the flavonoid chemical class. In order to extend the study, we designed an automated pipeline capable of searching natural product biosynthetic enzyme structures embedding ligandable catalytic sites. We collected structures of 117 biosynthetic enzymes. Finally, according to structural investigations of biosynthetic enzymes, we characterized diverse substrate-enzyme binding-modes, suggesting that natural product biological imprints usually do not agree with the key-lock odel. VI Statement of originality This work has not previously been submitted for a degree or diploma in any university. To the best of my knowledge and belief, the thesis contains no material previously published or written by another person except where due reference is made in the thesis itself. _____________________________ Brisbane, 7th October 2015 Noé Sturm VII Table of contents Acknowledgments _____________________________________________________ III Résumé ______________________________________________________________ V Abstract______________________________________________________________ VI Statement of originality ________________________________________________ VII Table of contents _____________________________________________________ VIII Common abbreviations ________________________________________________ XII Résumé (long) ________________________________________________________ XIII Summary _________________________________________________________ XXVIII Introduction _________________________________________________________ 34 Chapter 1. Development of a computational tool for binding site comparison ____ 39 1. SITEALIGN _____________________________________________________ 41 1.1. Overview of SiteAlign ________________________________________ 41 1.2. SiteAlign input ______________________________________________ 41 1.3. The sphere representation of protein binding sites _________________ 42 1.4. Scoring similarity between maps _______________________________ 47 1.5. Structural alignment _________________________________________ 51 2. SOLVENT ACCESSIBLE BINDING SITE DEFINITION ______________________ 52 2.1. Solvent accessibility filter _____________________________________ 52 2.2. Binding site delimitation ______________________________________ 56 2.3. Binding site mouth detection __________________________________ 57 2.4. Analysis of solvent accessible binding sites _______________________ 59 3. MODIFICATION OF SITEALIGN _____________________________________ 61 3.1. Physico-chemical descriptors __________________________________ 62 3.2. Topological descriptor _______________________________________ 63 3.3. Residue fingerprint __________________________________________ 64 3.4. Scoring function ____________________________________________ 64 3.5. Characterization of modifications impacting binding site comparison __ 65 4. BENCHMARKING VERSIONS OF SITEALIGN ___________________________ 71 4.1. Similarity threshold definition _________________________________ 71 4.2. Testing SiteAlign-5 against SiteAlign-4 ___________________________ 73 VIII CONCLUSION ______________________________________________________ 78 REFERENCES _______________________________________________________ 79 ANNEX 1 __________________________________________________________
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