Crystallographic mining of ASK1 regulators to unravel the intricate PPI interfaces for the discovery of small molecule

Abstract

Protein seldom performs biological activities in isolation. Understanding the protein-protein interactions' physical rewiring in response to pathological conditions or pathogen infection can help advance our comprehension of disease etiology, progression, and pathogenesis, which allow us to explore the alternate route to control the regulation of key target interactions, timely and effectively. Nonalcoholic steatohepatitis (NASH) is now a global public health problem exacerbated due to the lack of appropriate treatments. The most advanced anti-NASH lead compound (selonsertib) is withdrawn, though it is able to inhibit its target Apoptosis signal-regulating kinase 1 (ASK1) completely, indicating the necessity to explore alternate routes rather than complete inhibition. Understanding the interaction fingerprints of endogenous regulators at the molecular level that underpin disease formation and progression may spur the rationale of designing therapeutic strategies. Based on our analysis and thorough literature survey of the various key regulators and PTMs, the current review emphasizes PPI-based drug discovery's relevance for NASH conditions. The lack of structural detail (interface sites) of ASK1 and its regulators makes it challenging to characterize the PPI interfaces. This review summarizes key regulators interaction fingerprinting of ASK1, which can be explored further to restore the homeostasis from its hyperactive states for therapeutics intervention against NASH.

Keywords: ASK1; ASK1, Apoptosis signal-regulating kinase 1; CFLAR, CASP8 and FADD-like apoptosis regulator; CREG, Cellular repressor of E1A-stimulated genes; DKK3, Dickkopf-related protein 3; Interaction fingerprint; NAFLD, Non-alcoholic fatty liver disease; NASH; NASH, Nonalcoholic steatohepatitis; PPI, Protein-protein interaction; PTM, Post-trancriptional modification; PTMs; Protein-protein interaction; TNFAIP3, TNF Alpha Induced Protein 3; TRAF2/6, Tumor necrosis factor receptor (TNFR)-associated factor2/6; TRIM48, Tripartite Motif Containing 48; TRX, Thioredoxin; USP9X, Ubiquitin Specific Peptidase 9 X-Linked.