Studies of Staphylococcus aureus FabI inhibitors: fragment-based approach based on holographic structure-activity relationship analyses

Author(s)

Kronenberger, Thales ; Asse, Jr., Leonardo Rander ; Wrenger, Carsten ; Goulart Trossini, Gustavo Henrique ; Honorio, Kathia Maria ; Maltarollo, Vinicius Goncalves

• Document type: Journal article
• Source: Future Medicinal Chemistry; v. 9, n. 2, p. 135-151, JAN 2017.
• Web of Science Citations: 4

Abstract

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 (q(2) and r(pred)(2) 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. (AU)

• FAPESP's process: 14/03644-9 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/10288-1 - Analysis of the organelle biogenesis in Plasmodium falciparum by live cell imaging
• Grantee: Carsten Wrenger
• Support Opportunities: Regular Research Grants