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Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery |
| Phanankosi Moyo1, Luke Invernizzi1, Sephora M. Mianda1, Wiehan Rudolph1, Andrew W. Andayi2, Mingxun Wang3, Neil R. Crouch4,5, Vinesh J. Maharaj1 |
1. Department of Chemistry, Faculty of Natural and Agricultural Sciences, Biodiscovery Center, University of Pretoria, Private Bag X 20, Hatfield, Pretoria, 0028, South Africa;
2. Department of Physical and Biological Sciences, Murang'a University of Technology Murang'a, Murang'a, Kenya;
3. Computer Science and Engineering, University of California Riverside, 900 University Ave, Riverside, CA, 92521, USA;
4. Biodiversity Research and Monitoring Directorate, South African National Biodiversity Institute, Berea Road, P. O. Box 52099, Durban, 4007, South Africa;
5. School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4041, South Africa |
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Abstract The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria. Urgent measures need to be taken to curb this impending challenge. The higher plant-derived sesquiterpene, quinoline alkaloids, and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed. Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed. The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P. falciparum. To identify these novel scaffolds, we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data. Natural products were assigned to different structural classes using NPClassifier. To identify the most promising chemical scaffolds, we then correlated natural compound class with bioactivity and other data, namely (i) potency, (ii) resistance index, (iii) selectivity index and (iv) physicochemical properties. We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data. From this analysis we identified the top-ranked natural product pathway as the alkaloids. The top three ranked super classes identified were (i) pseudoalkaloids, (ii) naphthalenes and (iii) tyrosine alkaloids and the top five ranked classes (i) quassinoids (of super class triterpenoids), (ii) steroidal alkaloids (of super class pseudoalkaloids) (iii) cycloeudesmane sesquiterpenoids (of super class triterpenoids) (iv) isoquinoline alkaloids (of super class tyrosine alkaloids) and (v) naphthoquinones (of super class naphthalenes). Launched chemical space of these identified classes of compounds was, by and large, distinct from that of ‘legacy’ antimalarial drugs. Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs. These molecules have the potential to be developed into new antimalarial drugs.
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| Keywords
Natural products
Compound classes
Phytochemicals
Plasmodium falciparum
Antiplasmodial drug resistance
Malaria
Drug development
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| Fund:This research work was supported by a grant from the Department of Science and Innovation (DSI) of South Africa awarded to Vinesh Maharaj. The UP ISMC acknowledges the South African Medical Research Council as Collaborating Centre for Malaria Research. Phanankosi Moyo was supported by a grant from the University of Pretoria Postgraduate Research Support Bursary for his Postdoctoral Fellowship. Sephora Mianda Mutombo was supported by funds from the University of Pretoria Postgraduate Research Support Bursary, South Africa and the L’Oréal-UNESCO for Woman in Science grant. Luke Invernizzi was supported by funds from the National Research Foundation of South Africa. |
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Corresponding Authors:
Vinesh J. Maharaj,E-mail:vinesh.maharaj@up.ac.za
E-mail: vinesh.maharaj@up.ac.za
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Issue Date: 03 November 2023
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