# Structural Study of Selectivity Mechanisms for JNK3 and p38α with Indazole Scaffold Probing Compounds

## TL;DR

This study explores how certain compounds selectively bind to two important enzymes, JNK3 and p38α, using structural and simulation techniques to improve drug design.

## Contribution

The study reveals structural and dynamic mechanisms of selectivity for JNK3 and p38α using thiophene-indazole compounds and MD simulations.

## Key findings

- Crystal structures of inhibitors bound to JNK3 and p38α were determined.
- MD simulations identified key interactions governing selectivity and affinity.
- Findings offer insights to improve lead inhibitors for JNK3.

## Abstract

Selectivity is a primary focus in medicinal chemistry for ATP-competitive kinase inhibitors due to the highly conserved ATP binding pockets in the kinome. A decade of medicinal chemistry efforts has been carried out to develop selective inhibitors for JNKs, resulting in the identification of numerous promising scaffolds that even exhibit isoform selectivity. Thiophene-indazole is one of the scaffolds explored for isoform selectivity. Some iterations of this scaffold have also shown selectivity for p38α. In this study, we utilized four compounds derived from thiophene-indazole to investigate the mechanisms of selectivity for JNK3 and p38α. We determined crystal structures of the inhibitors bound to either JNK3 or p38α and subjected them to molecular dynamics (MD) simulations to understand the binding mechanism and critical interactions that govern affinity and selectivity for these two important kinases. The findings from this study provides valuable information for improving current lead inhibitors and developing a new generation of JNK3 isoform inhibitors.