Discovering small molecule binders of FIP200 that upregulate autophagy

National Center For Advancing Translational Sciences

Investigators

Abstract

During this reporting period, extensive SAR studies have been conducted on a DEL screening hit from NINDS. A range of assays that use binding and NMR are being utilized to drive SAR studies. Modelling studies at the CLAW dimer interface have identified secondary pockets that are being probed via virtual screening followed by compound purchase. A crystal structure of an ellipticine dimer has been obtained that has also initiated a campaign to find analogs with improved binding. Multiple chemical series are being pursued assisted with dynamic and static modeling. Initial assessment indicates flat SAR and dynamic simulation hints at considerable movement of residues at the CLAW dimer interface.