In silico assessment of natural products and approved drugs as potential inhibitory scaffolds targeting aminoacyl-tRNA synthetases from Plasmodium

Abstract

Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic interventions. Poor efficacy of the approved vaccine, and the rapid emergence of antimalarial drug resistance, warrants an urgent need to expedite the process of development of new lead molecules targeting malaria. Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes crucial for ribosomal protein synthesis and are valid antimalarial targets. This study explores the prospects of (re-)positioning the repertoire of approved drugs and natural products as potential malarial aaRS inhibitors. Molecular docking of these two sets of small-molecules to lysyl-, prolyl-, and tyrosyl-synthetases from Plasmodium followed by a comparison of the top-ranking docked compounds against human homologs facilitated identification of promising molecular scaffolds. Raltitrexed and Cefprozil, an anticancer drug and an antibiotic, respectively, showed stronger binding to Plasmodium aaRSs compared to human homologs with > 4 kcal/mol difference in the docking scores. Similarly, a difference of ~ 3 kcal/mol in Glide scores was observed for docked Calcipotriol, a drug used for psoriasis treatment, against the two lysyl-tRNA synthetases. Natural products such as Dihydroxanthohumol and Betmidin, having aromatic rings as a substructure, showed preferential docking to the purine binding pocket in Plasmodium tyrosyl-tRNA synthetase as evident from the calculated change in binding free energies. We present detailed analyses of the calculated intermolecular interaction for all top-scoring docked poses. Overall, this study provides a compelling foundation to design and develop specific antimalarials.

In silico Structure Prediction, Molecular Docking, and Dynamic Simulation of Plasmodium falciparum AP2-I Transcription Factor

“… 3 The licensed antimalarial drug’s poor efficacy, combined with the spread of antimalarial drug resistance, necessitates the development of an innovative strategy to identify novel antimalarial compounds. 4 …”

“…3 The licensed antimalarial drug's poor efficacy, combined with the spread of antimalarial drug resistance, necessitates the development of an innovative strategy to identify novel antimalarial compounds. 4 In silico techniques have been successful and have become powerful tools in the search to cure diseases, 5 reducing the use of animal models in pharmacological research, assisting in the rational design of novel and safe drug candidates, and repositioning marketed drugs. 6 They are vital in identifying viable therapeutic candidates at a low cost and time by using sophisticated computers and information technology to speed up drug discovery, lead optimization, drug development, and design.…”

“…David O Oladejo 1,2 , Gbolahan O Oduselu 3 , Titilope M Dokunmu 1,2 , Itunuoluwa Isewon 1,4 , Jelili Oyelade 1,4 , Esther Okafor 2 , Emeka EJ Iweala 1,2 and Ezekiel Adebiyi 1,4 The idea of targeting transcription and transcription factors (TFs) for drug therapy was long considered a "Sisyphean task," but recent work in drug discovery has shown the direct modulation of TF function by small molecules. [9][10][11] Transcription factors are proteins that bind to DNA sequences and control the stream of genetic information from DNA to mRNA.…”