Identification and Characterization of New Therapeutic Candidates for Naegleria fowleri- brain-eating Amoeba: A Multi-target Approach Based on 3D-QSAR, Molecular Docking, MM-GBSA, ADMET and Molecular Dynamics

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BACKGROUND: Naegleria fowleri is the most destructive and common brain-eating amoeba because it badly affects the human Central Nervous System (CNS), when amoeba in water goes up into the nose. N. fowleri also leads to PAM (primary amoebic meningoencephalitis) in humans. The lack of effective therapies for the treatment of PAM is a great drawback. The synthesis of new drug candidates for the treatment of this disease is time consuming and costly process. AIMS & OBJECTIVES: Therefore, to reduce time and cost, already FDA-approved brain cancer drugs can be repurposed to get an effective drug for the management of Naegleria fowleri because compounds used to treat brain cancer also have antiviral activities. METHODS: For this purpose, an appropriate three-dimensional (3D-QSAR) model was created using the IC50 values of anti-brain cancer drugs. The QSAR (quantitative structure activity relationship) can provide suitable input for determining the structure of brain cancer drugs against Naegleria fowleri. The model validation was used as statistical parameters like r2 and q2. RESULTS: An appropriate 3D-QSAR was carried out with q2 and r2 calculated values like 0.9935 and 0.7249. The model QSAR also showed the predicted activities of various currently available and new drugs for brain cancer. The study was followed by molecular docking and MD simulation. DISCUSSION: The results of docking study revealed that the protein 6W7G shows a high binding affinity with Harmol, the most active compound. MD simulation of 6G6R protein showed an RMSD value of about 0.35 Å. CONCLUSION: The present study indicated that the drug harmol could be an effective treatment for PAM in consideration of the 3D-QSAR, molecular docking, MD and ADME and toxicity analysis. However, further in vivo and in vitro studies are in process for the approval of this drug for the management of Naegleria fowleri.

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