A molecular modeling based screening for potential inhibitors to alpha hemolysin from Staphylococcus aureus

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Pharmacology

Background:

• Staphylococcus aureus infections are associated with alpha hemolysin, a toxin that damages cell membranes and induces apoptosis.
• Alpha hemolysin activity persists post-antibiotic treatment, contributing to hemostasis disturbances, thrombocytopenia, and pulmonary lesions.
• Inhibiting alpha hemolysin is a potential therapeutic strategy against staphylococcal infections.

Purpose of the Study:

• To identify novel compounds capable of inhibiting Staphylococcus aureus alpha hemolysin.
• To computationally screen a large library of compounds for potential alpha hemolysin inhibitors.
• To evaluate the pharmacokinetic and toxicity profiles of identified hit compounds.

Main Methods:

• Molecular docking simulations using AutoDock VINA were performed on 100,000 compounds from the ZINC database against the alpha hemolysin structure (PDB: 7AHL).
• Nine hit compounds were selected for further analysis.
• Pharmacokinetic and toxicity properties were predicted using PROTOX and FAFDrugs webservers.

Main Results:

• Two compounds, hit #1 ({[3a-(Dihydroxymethyl)-6-hydroxy-2,2-dimethyl-1,3,4-trioxatetrahydro-2H-pentalen-5-yl]methyl}amino(9H-fluoren-9-yl)acetate) and hit #2 (6-(Dihydroxymethyl)-2-{2-[3-(methylamino)propyl]-2-azatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,12,14-hexaen-6-yloxy}tetrahydro-2H-pyran-3,4,5-triol), showed significant binding affinities (-10.3 and -9.6 kcal/mol, respectively).
• These top two hits exhibited acceptable predicted toxicity and ADME (Absorption, Distribution, Metabolism, and Excretion) properties.
• The identified compounds are proposed as potential inhibitors of alpha hemolysin.

Conclusions:

• Computational screening identified two novel compounds with potential to inhibit Staphylococcus aureus alpha hemolysin.
• The identified compounds demonstrate favorable predicted pharmacokinetic and toxicity profiles.
• Further in vitro evaluation is warranted to confirm the inhibitory activity of these compounds.