In-silico Study of an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase (SAHH) of Naegleria fowleri using Molecular Docking, Density Functional Theory (DFT), and Molecular Dynamics (MD) Simulation.

Abstract

Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), a lethal disease with a mortality rate of 97%. Current treatment options are limited and often ineffective, highlighting the urgent need for novel therapeutic agents. This study aimed to identify potential inhibitors of the S-adenosyl-L-homocysteine hydrolase (SAHH) enzyme from N. fowleri using an in-silico approach including Molecular Docking, Density Functional Theory (DFT), Molecular Dynamics (MD) simulation, and Molecular Mechanics Generalized Born Surface Area (MMGBSA) analysis. This study included compounds capable of crossing the blood-brain barrier after screening the Asinex Library of 261120 compounds. After molecular docking, ligands had binding energies ranging from - 5.3 to - 11.4 kcal/mol. Only one ligand 2-[(3-Chlorobenzoyl)amino]-N-(2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-5-carboxamide had a better binding energy of - 11.4 kcal/mol as compared to the reference compound adenosine (- 10.1 kcal/mol). DFT calculations revealed HOMO-LUMO energy gaps of 0.14301 eV (α-spin) and 0.07565 eV (β-spin). MD simulations conducted throughout 100 ns confirmed the stable binding and interaction of the ligand with key active site residues, including Asp130, His232, Phe150, Leu200, and Lys68. Stable root-mean-square deviation (RMSD) and continuous interactions between the ligand and critical active site residues were observed. MMGBSA analysis confirmed the ligand's strong binding affinity, indicated by a negative binding energy with substantial lipophilic and Coulombic contributions. The selected ligand demonstrated significant binding affinity, stability, and inhibitory potential against NfSAHH, making it a promising candidate for further development as a therapeutic agent against PAM. The findings reveal novel binding interactions and structural insights into the binding mechanism of NfSAHH inhibitors. By employing a strategic in silico approach, this study provides a robust foundation for identifying and prioritizing potential inhibitors, optimizing resources for experimental validation, and streamlining the drug discovery process.