Prioritisation of Promising Therapeutic Targets in Plasmodium falciparum Using in Silico Multi Criteria Scoring

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Background: Malaria remains one of the deadliest infectious diseases globally, causing over 597,000 deaths each year, with Plasmodium falciparum (Pf) responsible for the most severe cases. Sub-Saharan Africa remains the most affected region of the world, the region hosting more than 90% of the global burden of P. falciparum. Despite years of research, drug resistance continues to emerge, underscoring the urgent need for new therapeutic targets. Aim: The aim of this study is to identify promising therapeutic targets in Plasmodium falciparum using advanced in silico approaches. This study focuses particularly on the intraerythrocytic stage of the parasite's life cycle, which is critical for its survival and proliferation. Methodology: A comprehensive bioinformatics approach was employed, integrating data mining and extensive database analyses to efficiently streamline the drug discovery pipeline and pinpoint vital therapeutic targets in Plasmodium falciparum. Analyses were carried out from January to June 2022 at the African Centre of Excellence in Bioinformatics (ACE-Mali), using data from the TDR Targets database and advanced bioinformatics tools. The WHO validated TDR Targets database was used to extract Plasmodium falciparum proteins likely to be therapeutic targets, applying strict criteria such as strong expression during the intra-erythrocytic stage, lack of human orthologs, essentiality, druggability score and bibliographic support. This candidate list has been refined using an in-house scoring system combining bioinformatics analyses, taking into account criteria such as the presence of transmembrane helices, sequence identity, and conservation. Each criterion was scored from 0 to 3 and summed into an overall prioritisation score to systematically rank proteins. Results: The study identified sixteen potential therapeutic targets, with five of them: Adenylate kinase, P. falciparum Chloroquine Resistance Transporter (PfCRT), AdenyloSuccinate Lyase (ADSL), PhosphatidylSerine Decarboxylase (PSD), and Protein Disulfide Isomerase (PDI), highlighted as highly promising. These key proteins are involved in essential processes such as invasion, replication, and immune evasion of the malaria parasite. Conclusion: This study identified sixteen potential therapeutic targets against malaria, with Adenylate kinase, PfCRT, ADSL, PSD, and PDI standing out as particularly promising. These targets may contribute to overcoming drug resistance and support global eradication efforts. The findings highlight the power of in silico approaches in accelerating drug discovery and target validation.

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