Evaluation of Colchicine’s interaction with the ATP-binding region of mice NLRP3-NACHT domain using molecular docking and dynamics simulation

Abstract

Since the discovery of the role of NLRP3 in microbial infection in 2001, many studies have shown that NLRP3 play a key role in causing many mammal acute and chronic diseases. However, a full understanding of the mechanism of NLRP3 activation is still lacking. Our previous theoretical work and experimental evidence show the role of ATP in interacting with and activating the NATCH region of NLRP3. In this study, we continue to use bioinformatics and molecular dynamic (MD) simulation to evaluate the competitive impact of the interaction the ligand ATP and colchicine (COL) with this NACHT protein. The later ligand is a medication to treat gout attacks. Our results show that COL bind stably to the ATP binding pocket of mice NACHT domain with high numbers of hydrophobic and van der Waals interactions, while hydrogen bond and electrostatic interactions are important types of contact for keeping ATP at its NACHT pocket. Our results assist in building in-silico screening model for natural compounds with pharmacological effects to NLRP3 similar to colchicine with few side effects. In addition, this work helps to better understand the balance between this inflammasome activation and inhibition, which will help in the improvement and development of new therapies for related diseases.

The Role of Colchicine in Atherosclerosis: From Bench to Bedside

“…Monocyte caspase-1 inhibition has been detected in ACS patients as well [ 64 ]. Very recently, using molecular dynamic simulation in a mouse model, it has been proposed that colchicine could interact with the ATP binding region of the NLRP3-NACHT domain, thus potentially precluding inflammasome activation [ 93 ]. Similarly, in ATP-mediated NLRP3 inflammasome activation, formation of P2X7 pores is a key step [ 94 ].…”