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In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design
Dissertation (MSc)--University of Pretoria, 2017.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2017
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| _version_ | 1867613676814467072 |
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| access_status_str | Open Access |
| author2 | Cromarty, Allan Duncan |
| author_browse | Cromarty, Allan Duncan |
| author_facet | Cromarty, Allan Duncan |
| collection | Thesis |
| dc_rights_str_mv | © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Dissertation (MSc)--University of Pretoria, 2017. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/63045 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:39:56.368Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2017 |
| publishDateRange | 2017 |
| publishDateSort | 2017 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/63045 In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design Cromarty, Allan Duncan dmatlebjane@ymail.com Birkholtz, Lyn-Marie Matlebjane, Dikeledi M.A. Malaria Plasmodium falciparum In silico design CDPK FIKK Kinase Bromodomain protein ATP-binding site Stage specificity Kill kinetics Health sciences theses SDG-03 Health sciences theses SDG-09 Health sciences theses SDG-17 Dissertation (MSc)--University of Pretoria, 2017. Malaria is a major public health problem that affects millions of lives globally. The increased burden of malaria requires new interventions that will address the eradication of the disease. Current interventions include vector control by using insecticide-treated bed nets and indoor residual spraying, and antimalarial drugs to control the parasite. Parasite resistance has been reported for the currently used effective antimalarial drugs. To pre-empt the impact of parasite resistance a continued development of new antimalarial drugs that have novel mechanisms of action should be pursued. Antimalarial drug discovery requires that potential antimalarial drugs should have different drug targets to those already targeted, to lower the chances of resistance. Potential antimalarial drugs should preferably provide a single radical cure to prevent reproduction at all life cycle stages. This study tested the effects of in silico designed compounds targeting plasmodial Ca2+- dependent protein kinases (CDPK) 1 & 4, FIKK kinases and bromodomain proteins on the Plasmodium parasite. These enzymes are involved in gene regulation and are important factors during gene transcription. In P. falciparum the gatekeeper kinases contain small hydrophobic pockets near the ATP-binding site. These hydrophobic pockets allow for selective inhibition of these proteins at the ATP-binding site. The compounds were tested in vitro to determine their antiplasmodial activity. These compounds are shown to be potential inhibitors of the intra-erythrocytic P. falciparum parasites as three of the compounds showed selective cytotoxic activity at less than 1 μM against the chloroquine sensitive laboratory strains (3D7 and NF54). Even though the proteins targeted by these compounds have been previously indicated to play a role at specific stages during the parasite’s life cycle, the compounds tested here were not able to target the sexual gametocyte stages of the Plasmodium parasite. Further optimisation of these compounds should be performed to improve activity against both the asexual and sexual stages of the parasites. em2026 Pharmacology MSc Unrestricted SDG-03: Good health and well-being SDG-09: Industry, innovation and infrastructure SDG-17: Partnerships for the goals 2017-11-07T07:43:08Z 2017-11-07T07:43:08Z 2017 2017 Dissertation Matlebjane, DM 2017, In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design, MSc Dissertation, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/63045> http://hdl.handle.net/2263/63045 en © 2017 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | Malaria Plasmodium falciparum In silico design CDPK FIKK Kinase Bromodomain protein ATP-binding site Stage specificity Kill kinetics Health sciences theses SDG-03 Health sciences theses SDG-09 Health sciences theses SDG-17 In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title | In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title_full | In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title_fullStr | In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title_full_unstemmed | In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title_short | In vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| title_sort | in vitro efficacy assessment of targeted antimalarial drugs synthesized following in silico design |
| topic | Malaria Plasmodium falciparum In silico design CDPK FIKK Kinase Bromodomain protein ATP-binding site Stage specificity Kill kinetics Health sciences theses SDG-03 Health sciences theses SDG-09 Health sciences theses SDG-17 |
| url | http://hdl.handle.net/2263/63045 |