Fig. 7: Molecular dynamics and structure-activity relationship data provide insights into interactions contributing to isoxazole 1/2-CnAcs1 binding.
From: Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
A Histogram of molecular dynamics interactions of isoxazole 1 with CnAcs1. B Schematic indicating residues predicted to contribute to the binding of isoxazole 1 to CnAcs1. The majority of residues predicted to contribute to binding participate in hydrophobic interactions (green). A key H-bonding interaction between T336 and the amide carbonyl of isoxazole 1 was identified in 81% of simulations. For panels A&B, charged interactions are shown in orange; hydrophobic in green; polar in blue; water in grey, and solvent exposed in light grey. C SAR of the isoxazole scaffold. IC50 data for isoxazoles 2–13 indicate that the amide carbonyl (isoxazole 3/4), isoxazole cyclopropyl moiety (isoxazoles 5–7), and an inductively electronegative substituent at the para-position of the aryl ring (isoxazoles 2, 9, and 11) are key drivers of CnAcs1 potency. Source data are provided as a Source data file, and the molecular dynamics files have been deposited at FigShare (see data availability statement for link).
