The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has necessitated new drugs. Selective estrogen receptor modulators are in clinical use for the prevention and treatment of breast cancer and postmenopausal osteoporosis.
The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.
Malaria is one of the major global health concerns still prevailing in this 21st century. Even the effect of artemisinin combination therapies (ACT) have declined and causing more mortality across the globe. Therefore, it is important to understand the basic biology of malaria parasite in order to find novel drug targets. Helicases play important role in nucleic acid metabolism and are components of cellular machinery in various organisms. In this manuscript we have performed the biochemical characterization of homologue of DDX17 from Plasmodium falciparum (PfDDX17). Our results show that PfDDX17 is an active RNA helicase and uses mostly ATP for its function. The qRT-PCR experiment results suggest that PfDDX17 is highly expressed in the trophozoite stage and it is localised mainly in the cytoplasm and in infected RBC (iRBC) membrane mostly in the trophozoite stage. The dsRNA knockdown study suggests that PfDDX17 is important for cell cycle progression. These studies report the biochemical functions of PfDDX17 helicase and further augment the fundamental knowledge about helicase families of P. falciparum .
Proteases regulate cell proliferation, cell growth, biological processes, and overall homeostasis. Several proteases are extensively annotated and well-characterized in pathogenic organisms such as bacteria, parasites, and microbial species as anti-bacterial, anti-parasitic and anti-microbial. Several of these proteins are being explored as viable targets for various drug discovery research in various microbial diseases. Despite multiple studies on pathogen proteases, the comprehensive information on pathogen proteases is scattered or redundant, if available. We have developed a comprehensive and integrative protease database resource, ProtPathDB, for 23 pathogen species distributed among five taxa, Amoebozoa, Apicomplexa, Heteroloblosea, Kinetoplastida and Fungi. ProtPathDB collects and organizes sequences, class division, signal peptides, localization, post-translational modifications, three-dimensional structure and related structural information regarding binding sites, and binding scores of annotated proteases. The ProtPathDB is publicly available at http://bioinfo.icgeb.res.in/ProtPathDB. We believe that the database will be a one-stop resource for integrative and comparative analysis of pathogen proteases to better understand the functions of the microbial proteases and help drug discovery efforts target proteases.
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