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South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches
The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891524/ https://www.ncbi.nlm.nih.gov/pubmed/31703388 http://dx.doi.org/10.3390/molecules24224036 |
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author | Musyoka, Thommas Bishop, Özlem Tastan |
author_facet | Musyoka, Thommas Bishop, Özlem Tastan |
author_sort | Musyoka, Thommas |
collection | PubMed |
description | The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2. |
format | Online Article Text |
id | pubmed-6891524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68915242019-12-18 South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches Musyoka, Thommas Bishop, Özlem Tastan Molecules Article The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2. MDPI 2019-11-07 /pmc/articles/PMC6891524/ /pubmed/31703388 http://dx.doi.org/10.3390/molecules24224036 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Musyoka, Thommas Bishop, Özlem Tastan South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title | South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title_full | South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title_fullStr | South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title_full_unstemmed | South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title_short | South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches |
title_sort | south african abietane diterpenoids and their analogs as potential antimalarials: novel insights from hybrid computational approaches |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891524/ https://www.ncbi.nlm.nih.gov/pubmed/31703388 http://dx.doi.org/10.3390/molecules24224036 |
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