Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design
Abstract Background Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other...
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ftdoajarticles:oai:doaj.org/article:ccde157f5b58467493ebbe343bf89440 2023-05-15T15:16:17+02:00 Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design Thommas Mutemi Musyoka Joyce Njoki Njuguna Özlem Tastan Bishop 2019-05-01T00:00:00Z https://doi.org/10.1186/s12936-019-2790-2 https://doaj.org/article/ccde157f5b58467493ebbe343bf89440 EN eng BMC http://link.springer.com/article/10.1186/s12936-019-2790-2 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2790-2 1475-2875 https://doaj.org/article/ccde157f5b58467493ebbe343bf89440 Malaria Journal, Vol 18, Iss 1, Pp 1-21 (2019) Cysteine protease Falcipain Zymogen Prodomain inhibitory segment Homology modelling Binding affinity Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2019 ftdoajarticles https://doi.org/10.1186/s12936-019-2790-2 2022-12-31T09:26:09Z Abstract Background Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors. Methods Sequence and structure variations between prodomain regions of plasmodial proteins and human cathepsins were determined using in silico approaches. Additionally, evolutionary clustering of these proteins was evaluated using phylogenetic analysis. High quality partial zymogen protein structures were modelled using homology modelling and residue interaction analysis performed between the prodomain segment and mature domain to identify key interacting residues between these two domains. The resulting information was used to determine short peptide sequences which could mimic the inherent regulatory function of the prodomain regions. Through flexible docking, the binding affinity of proposed peptides on the proteins studied was evaluated. Results Sequence, evolutionary and motif analyses showed important differences between plasmodial and human proteins. Residue interaction analysis identified important residues crucial for maintaining prodomain integrity across the different proteins as well as the pro-segment responsible for inhibitory mechanism. Binding affinity of suggested peptides was highly dependent on their residue composition and length. ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 18 1 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Cysteine protease Falcipain Zymogen Prodomain inhibitory segment Homology modelling Binding affinity Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
spellingShingle |
Cysteine protease Falcipain Zymogen Prodomain inhibitory segment Homology modelling Binding affinity Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Thommas Mutemi Musyoka Joyce Njoki Njuguna Özlem Tastan Bishop Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
topic_facet |
Cysteine protease Falcipain Zymogen Prodomain inhibitory segment Homology modelling Binding affinity Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors. Methods Sequence and structure variations between prodomain regions of plasmodial proteins and human cathepsins were determined using in silico approaches. Additionally, evolutionary clustering of these proteins was evaluated using phylogenetic analysis. High quality partial zymogen protein structures were modelled using homology modelling and residue interaction analysis performed between the prodomain segment and mature domain to identify key interacting residues between these two domains. The resulting information was used to determine short peptide sequences which could mimic the inherent regulatory function of the prodomain regions. Through flexible docking, the binding affinity of proposed peptides on the proteins studied was evaluated. Results Sequence, evolutionary and motif analyses showed important differences between plasmodial and human proteins. Residue interaction analysis identified important residues crucial for maintaining prodomain integrity across the different proteins as well as the pro-segment responsible for inhibitory mechanism. Binding affinity of suggested peptides was highly dependent on their residue composition and length. ... |
format |
Article in Journal/Newspaper |
author |
Thommas Mutemi Musyoka Joyce Njoki Njuguna Özlem Tastan Bishop |
author_facet |
Thommas Mutemi Musyoka Joyce Njoki Njuguna Özlem Tastan Bishop |
author_sort |
Thommas Mutemi Musyoka |
title |
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
title_short |
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
title_full |
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
title_fullStr |
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
title_full_unstemmed |
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
title_sort |
comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide based inhibitor design |
publisher |
BMC |
publishDate |
2019 |
url |
https://doi.org/10.1186/s12936-019-2790-2 https://doaj.org/article/ccde157f5b58467493ebbe343bf89440 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 18, Iss 1, Pp 1-21 (2019) |
op_relation |
http://link.springer.com/article/10.1186/s12936-019-2790-2 https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2790-2 1475-2875 https://doaj.org/article/ccde157f5b58467493ebbe343bf89440 |
op_doi |
https://doi.org/10.1186/s12936-019-2790-2 |
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Malaria Journal |
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18 |
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1 |
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1766346570202087424 |