Studies of Staphylococcus aureus FabI inhibitors: fragment-based approach based on holographic structure-activity
Thales Kronenberger1, Leonardo Rander Asse2, Carsten Wrenger1
1Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo, SP 05508-000, Brazil.
Aim:
FabI is a key enzyme in the fatty acid metabolism of Gram-positive bacteria such as Staphylococcus aureus and is an established drug target for known antibiotics such as triclosan. However, due to increasing antibacterial resistance, there is an urgent demand for new drug discovery. Recently, aminopyridine derivatives have been proposed as promising competitive inhibitors of FabI.
Methods:
In the present study, holographic structure-activity relationship (HQSAR) analyses were employed for determining structural contributions of a series containing 105 FabI inhibitors.
Results & Conclusion:
The final HQSAR model was robust and predictive according to statistical validation (q2 and r2pred equal to 0.696 and 0.854, respectively) and could be further employed to generate fragment contribution maps. Then, final HQSAR model together with FabI active site information can be useful for designing novel bioactive ligands.
