Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Biology

Background:

• Spindlin1 is a chromatin reader protein implicated in epigenetic regulation and various cancers.
• The lead inhibitor A366 provides a starting point for developing novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel Spindlin1 inhibitors with improved activity and selectivity.
• To explore the structure-activity relationship (SAR) of A366 analogs.
• To identify a rapid in silico method for predicting compound activity.

Main Methods:

• Synthesis and in vitro testing of 21 A366 derivatives.
• Molecular modeling, including docking and molecular dynamics (MD) simulations.
• MM-GBSA calculations for pose rescoring and selectivity profiling against G9a and GLP.

Main Results:

• Identified key structural features for Spindlin1 inhibition: a charged pyrrolidine, aromatic cage, propyloxy linker, and 2-aminoindole core with an amidine group.
• MM-GBSA successfully discriminated between active and inactive compounds.
• Compounds 1s and 1t exhibited nanomolar Spindlin1 activity and selectivity over G9a and GLP.

Conclusions:

• Novel Spindlin1 inhibitors based on the A366 scaffold were successfully developed.
• The study elucidated critical structural requirements for Spindlin1 inhibition.
• Compounds 1s and 1t represent promising leads for epigenetic cancer therapy.