The International Workshop on New Approaches in Drug Design & Discovery

Organized by Prof. Gerhard Klebe and Prof. Christoph Sotriffer . More information about the conference here

I presented a poster DOCKING STUDY AND BINARY CLASSIFICATION MODEL OF ISOTHIAZOLONES AS IRREVERSIBLE INHIBITORS OF THE HISTONE ACETYLTRANSFERASE PCAF..

ABSTRACT:

Aryl and alkyl N-substituted isothiazolone compounds have been shown to inhibit the histone acetyltransferase (HAT) PCAF and p300 irreversibly. In this series of aryl and alkyl N-substituted isothiazolones, the inhibition is due to the irreversible interaction with thiol groups of the enzyme. PCAF inhibition of isothiazolones is abolished in the presence of thiol-reducing agents like dithiothreitol (DTT). Furthermore, the activity was not restored in experiments involving the incubation of PCAF with two isothiazolones followed by dialysis for 24 hours.

• Series of isothiazolones have been identified as irreversible PCAF inhibitors.
• Non-covalent and covalent docking of these compounds proved the accessibility of the SN-bond in isothiazolones to the thiol group of Cys574.
• The activity of irreversible inhibitors is related not only to the molecular recognition between the inhibitor and the protein, but also to the reactivity of the ligands and the nucleophilic softness of the thiol group in the protein.
• We found that QM descriptors related to frontier MO theory can describe the reactivity and give good classification models for the studied isothiazolones.