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Identification of Potential Drug Targets in Erythrocyte Invasion Pathway of Plasmodium falciparum

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Abstract

The erythrocyte invasion phase plays a critical role in multiplication, sexual determination, and drug resistance in Plasmodium falciparum. In order to identify the critical genes and pathways in the erythrocyte invasion phase, the gene set (GSE129949) and the RNA-Seq count data for the W2mef strain were used for further analysis. An integrative bioinformatics study was performed to scrutinize genes as potential drug targets. 487 differentially expressed genes (DEGs) with an adjusted P value < 0.001 enriched 47 Gene Ontology (GO) terms that were over-represented based on hyper-geometric analysis P value < 0.01. Protein–Protein interaction network analysis was done using DEGs with higher confidence interactions (PPI score threshold = 0.7). MCODE and cytoHubba apps were utilized to define the hub proteins and rank them based on multiple topological analyses and MCODE scores. Furthermore, Gene Set Enrichment Analysis (GSEA) was carried out by using 322 gene sets from the MPMP database. The genes involved in multiple significant gene sets were determined by leading-edge analysis. Our study identified six genes encoding proteins that could be potential drug targets involved in the erythrocyte invasion phase related to merozoites motility, cell-cycle regulation, G-dependent protein kinase phosphorylation in schizonts, control of microtubule assembly, and sexual commitment. The druggability of those proteins was calculated based on the DCI (Drug Confidence Index) and predicted binding pockets’ values. The protein that showed the best binding pocket value was subjected to deep learning-based virtual screening. The study identified the best small molecule inhibitors in terms of drug-binding score against the proteins for inhibitor identification.

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Acknowledgements

The authors would like to acknowledge the Bioinformatics lab facility of the School of Biotechnology, KIIT Deemed to be University, Bhubaneswar during the course of work.

Funding

The project work is supported by the SERB-MATRICS project (MTR/2021/000191) from Department of Science and Technology, Govt. of India awarded to Dr. Rajani Kanta Mahapatra.

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Authors and Affiliations

  1. School of Biotechnology, KIIT Deemed to be University, Bhubaneswar, Odisha, 751024, India

    Mohammad Mustafa Kazan, Misgana Mengistu Asmare & Rajani Kanta Mahapatra

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  2. Misgana Mengistu Asmare
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Contributions

MMK has developed the bioinformatics pipeline and performed the RNA-Seq data analysis. MMA contributed towards the druggability and virtual screening results. RKM supervised the whole study and corrected the manuscript.

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Correspondence to Rajani Kanta Mahapatra.

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Kazan, M.M., Asmare, M.M. & Mahapatra, R.K. Identification of Potential Drug Targets in Erythrocyte Invasion Pathway of Plasmodium falciparum. Curr Microbiol 80, 165 (2023). https://doi.org/10.1007/s00284-023-03282-4

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