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- Title
DRUG REPURPOSING TOWARDS THE IDENTIFICATION OF NOVEL ANTI-LEISHMANIA MOLECULES TARGETING THE METHYLTHIOADENOSINE PHOSPHORYLASE.
- Authors
MOUSSA, Z.; HARIGUA-SOUIAI, E.; BARHOUMI, M.; GUIZANI, I.
- Abstract
Introduction and Objectives: Leishmaniases are vector-bourne diseases caused by kinetoplastidae of the genus Leishmania. They constitute major public health problems worldwide. The current drugs are toxic, costly and in most cases inefficient. Thus, developing new anti-Leishmania drugs is a research priority. Nevertheless, drug discovery is a highly cost-intensive process. In this context we conducted a structure-based drug discovery approach based on drug repurposing, which relies on discovering new applications for drugs that are already approved and available in the market. We focused on the Leishmania infantum Methylthioadenosine phosphorylase (LiMTAP), a homotrimeric enzyme that plays a crucial role in three metabolic pathways, namely the purine and methionine salvage pathways and the polyamine pathway. Methods: We modeled the 3D structure of this protein using multiple methods. The model with the highest quality was retained and used to develop the trimeric structure model of the protein. In fact, the quaternary structure is crucial to define the active site (AS) of LiMTAP, which is embedded between two adjacent monomers. We then performed the docking of methylthioadenosine (MTA), the natural substrate, and a sulfate ion as a co-factor on the defined AS. Interactions that are characteristic of the MTA-MTAPs were obtained, along with interactions specific to LiMTAP as compared to the mammalian orthologue. Then, we performed a virtual screening of the FDA-approved drugs collection against the AS of LiMTAP. We selected the most promising molecules as follows: (i) their belonging to the anti-infectious class, (ii) having binding energies better than the MTA and (iii) presenting high chemical similarity to MTA, as the efficacy of transition-state inhibitors was proven on MTAP proteins in human and Trypanosoma brucei, a related kinetoplastid parasite. Three molecules were identified as potential anti-LiMTAP effectors having leishmanicidal properties. Conclusion: To conclude, through a cost-effective computational approach we could predict three novel transition-state inhibitors of LiMTAP enzyme with potential anti-Leishmania effects. We will further confirm their effects on the enzymatic activity of the recombinant protein and on the viability of the promastigote and amastigote form of Leishmania parasites.
- Subjects
LEISHMANIASIS; METHYLTHIOADENOSINE; POLYAMINES; MONOMERS; ENZYMES
- Publication
Archives de l'Institut Pasteur de Tunis, 2020, Vol 97, Issue 1-4, p31
- ISSN
0020-2509
- Publication type
Article