Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

Abstract

Background Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat. Methods The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases. Results The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045–917-542 as a promising inhibitor of PfAp4AH among prioritized targets. Conclusion The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

“…Within a set of 1,356 proteins qualifying as dually modifiable, a common set between the prediction results and curated datasets/databases unveiled 167 proteins exhibiting propensities for both palmitoylation and phosphorylation ( Figure 1 and Supplementary Table 6 ). These 167 dually modified proteins were screened for essentiality using existing literature and systematic database searches ( Aurrecoechea et al., 2009 ; Ali et al., 2021 ; Bateman et al., 2021 ). Based on this, four dually modified proteins, namely, PMII (plasmepsin II), ADA (adenosine deaminase), CDPK1, and MTIP, were found to be essential for parasite IED and invasion having no paralogs in human hosts ( Ali et al., 2021 ) ( Figure 4A and Supplementary Table 6 ).…”

“…A high confidence list of essential parasitic factors with no paralogs in the human host proteome was prepared from the intersection subset (A∩B) of curated database searches and literature mining results. ( Ali et al., 2021 ; Bateman et al., 2021 ; Amos et al., 2022 ). The dually modified proteins were subsequently mapped to the essential proteins.…”

Deciphering the Role of Protein Phosphatases in Apicomplexa: The Future of Innovative Therapeutics?

“…From this screening, two Ser/Thr phosphatases: PP6 and PP4, were identified based on their sub-cellular localization, their structure, and the absence of host homologs. PP4 was even shortlisted as one of the most promising potential targets due to some promising structural features such as druggable pockets or the fact that it may be important component of the Plasmodium metabolic network [146]. In a recent study, Pandey et al carried out an in silico virtual screening of the ChEMBL-NTD library using the Plasmodium falciparum phosphatase of regenerating liver (Pf PRL) as a drug target [147].…”

“…Recently, Ali et al created a list of anti-malaria potential drug targets to be prioritized for further investigation. P. falciparum proteins previously identified as essential for parasite blood development were subjected to in silico analysis to assess their druggability potential [ 146 ]. From this screening, two Ser/Thr phosphatases: PP6 and PP4, were identified based on their sub-cellular localization, their structure, and the absence of host homologs.…”

“…From this screening, two Ser/Thr phosphatases: PP6 and PP4, were identified based on their sub-cellular localization, their structure, and the absence of host homologs. PP4 was even shortlisted as one of the most promising potential targets due to some promising structural features such as druggable pockets or the fact that it may be an important component of the Plasmodium metabolic network [ 146 ].…”