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Drug Discovery Against Leishmaniasis Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 265 Drug discovery against leishmaniasis Bio- and chemoinformatic guided strategies for target evaluation and hit identification ELISABET VIKEVED ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-513-0521-9 UPPSALA urn:nbn:se:uu:diva-368499 2019 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC, Husargatan 3, Uppsala, Friday, 1 February 2019 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor David Horn (The Wellcome Trust Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee). Abstract Vikeved, E. 2019. Drug discovery against leishmaniasis. Bio- and chemoinformatic guided strategies for target evaluation and hit identification. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 265. 67 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0521-9. Leishmaniasis is a neglected tropical disease mainly affecting poor people in developing countries. It is caused by infections of flagellated protozoa belonging to genus Leishmania. The few available drugs are associated with problems such as low effectiveness, severe side effects and resistance development. The overall aim of this thesis is to aid in drug discovery against leishmaniasis – primarily using bio- and chemoinformtic approaches. In the first part of the thesis potential drug targets in Leishmania parasites were identified and hits against these targets were thereafter suggested. In paper I bioinformatics together with experimental work were used to evaluate lateral gene transfer (LGT) in genus Leishmania. LGTs of prokaryote origin often lack human homologs, and are therefore hypothesized to be valuable drug targets. LGT in genus Leishmania is shown to be a dynamic process in which some acquired genes are conserved in the recipient genomes and others are degraded and eventually lost. Some LGTs have also undergone pseudogenization. It is thus important to evaluate LGT products before exploring them as potential drug targets. In paper II ligand-based virtual screening and molecular docking were used to suggest potential hits against the LGT product pteridine reductase 1 (PTR1) and the two-domain enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) both involved in folate metabolism. DHFR-TS is not encoded by an LGT but it has been hypothesised that several enzymes in the folate pathway need to be inhibited to affect the viability of Leishmania parasites. One potential hit compound against PTR1 and the DHFR-domain and four hit compounds against PTR1 and the TS-domain were identified and tested on Leishmania tropica promastigotes. The suggested PTR1/TS inhibitors had no effect in the promastigote assay, however one of them enhanced the effect of the PTR1/DHFR inhibitor, which also had effect on its own. In the second part of the project, focus shifted towards predictions of targets for compounds with known anti-leishmanial activity but unknown mechanisms of actions. In paper III a ligand- based-target fishing (LBTF) method was developed. The reference compounds were metabolites to metabolic enzymes and similarities were assessed with Euclidean distance calculations in chemical property space. The LBTF approach was used to suggest potential targets to a set of anti-leishmanial agents retrieved from ChEMBL-database. The theory behind the LBTF method developed in paper III was also used in paper IV to predict targets of two sponge-derived alkaloids that where shown to have anti-leishmanial activity. Keywords: Leishmaniasis, Drug discovery, Lateral gene transfer, Comparative genomics, Virtual screening, Target fishing, Marine natural products Elisabet Vikeved, Department of Medicinal Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden. © Elisabet Vikeved 2019 ISSN 1651-6192 ISBN 978-91-513-0521-9 urn:nbn:se:uu:diva-368499 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-368499) ”The voices of a million angels could not express my gratitude All that I am, and ever hope to be I owe it all to Thee To God be the glory” (Andraé Crouch) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Vikeved, E., Backund, A., Alsmark, C. (2016) The Dynamics of Lateral Gene Transfer in Genus Leishmania - A Route for Adapta- tion and Species Diversification. PLoS Negl Trop Dis, 10(1): e0004326 II Vikeved, E., Sköld, C., Alsmark, C. Multi-targeting the folate path- way is a promising strategy against Leishmania tropica. (Manu- script) III Vikeved, E., Alsmark, C., Sköld C. Prediction of anti-leishmanial drug targets using metabolite-based target fishing. (Manuscript) IV Strömstedt, AA., Vikeved, E., Cardenas, P., Alsmark, C., Chen, YH. and Backlund, A. Aaptamines from Haliclona and bromopyrroles from Agelas — marine sponge alkaloids with distinct modes of ac- tion against bacteria and protozoa. (Manuscript) Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Neglected tropical diseases ....................................................................... 11 Leishmaniasis ........................................................................................... 11 Leishmania parasites ............................................................................ 12 Current treatments and their challenges ............................................... 13 Drug discovery against leishmaniasis ....................................................... 14 Target validation .................................................................................. 14 Phenotypic screening ........................................................................... 19 Drug repurposing ................................................................................. 20 Natural products in drug discovery .......................................................... 20 Aims .............................................................................................................. 22 Part I. Identification of valuable targets and searching for potential hits ..... 23 Evaluation of LGTs as potential drug targets (paper I) ........................... 23 Methods ................................................................................................ 23 Results and Discussion ........................................................................ 25 Conclusions .......................................................................................... 30 Identification and evaluation of compounds targeting LGT products and other enzymes in Leishmania folate metabolism (paper II) .................... 31 Methods ................................................................................................ 32 Results and Discussion ........................................................................ 34 Conclusions .......................................................................................... 37 Part II. Suggesting potential targets for anti-leishmanial hit compounds ..... 38 Development of a ligand-based target fishing approach (Paper III) ....... 38 Methods ................................................................................................ 38 Results and Discussion ........................................................................ 41 Conclusions .......................................................................................... 46 Evaluation of marine alkaloids against Leishmania parasites and predicting possible targets for these (paper IV) ...................................... 47 Methods ................................................................................................ 48 Results and Discussion ........................................................................ 49 Conclusions .......................................................................................... 53 Concluding remarks ...................................................................................... 54 Populärvetenskaplig sammanfattning ........................................................... 55 Acknowledgment .......................................................................................... 58 References ..................................................................................................... 60 Abbreviations C. albicans Candida albicans CAI Codon adaptation index CCRF-CEM Blood T lymphoblast cancer cell line CL Cutaneous leishmaniasis DHFR-TS Dihydrofolate reductase-thymidylate synthase DLD-1 Colon epithelial cancer cell line DNDi Drugs for Neglected Disease initiative dUMP Deoxyuridine monophaspahte E. coli Escherichia coli ED Euclidean distance EF-TU Elongation factor thermo unstable HIS Human enzyme inhibitory set HIS-PT Human enzyme inhibitory set (with) predicted targets HMS Human metabolite set HSP 70 Heat shock protein 70 IC50 Half-maximal inhibitory concentration K562 Bone marrow lymphoblast cancer cell line Ka/Ks Non-synonymous/synonymous substitutions L. braziliensis Leishmania braziliensis L. infantum Leishmania infantum L. major Leishmania major L. mexicana Leishmania mexicana L. tarentolae Leishmania tarentolae L. tropica Leishmania tropica LBTF Ligand-based target fishing LDS Leishmanicidal set LGT Lateral gene transfer LGTs
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