Identification of novel compound against STAT3 mediated liver fibrosis: An MD simulation based study

Abstract

Liver fibrosis, characterized by the pathological accumulation of extracellular matrix in response to chronic liver injury, represents a significant global health concern. Signal Transducer and Activator of Transcription 3 (STAT3) have been identified as a critical mediator in the fibrotic process, making it an attractive target for therapeutic intervention. This study aimed to computationally design a novel inhibitor against STAT3, utilizing bioactive compounds derived from Ricinus communis, a plant recognized for its hepatoprotective properties. 30 bioactive compounds from Ricinus communis were initially screened through molecular docking with STAT3, followed by further evaluation of the top 10 compounds using Swiss ADME for pharmacokinetic parameters and drug-like properties. Subsequently, (5beta)Pregnane-3,20beta-diol, 14alpha, 18alpha-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate was selected based on its robust binding affinity and favorable Swiss ADME profile, demonstrating potential stability in complex with STAT3 through molecular dynamics (MD) simulations. Analysis of MD simulation trajectories indicated stable interactions between STAT3 and (5beta)Pregnane-3,20beta-diol, 14alpha,18alpha-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate, as evidenced by RMSD, RMSF, Rg, SASA and binding free energy values. In conclusion, These findings position (5β)Pregnane-3,20β-diol, 14α.,18α.-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-diacetate as a promising inhibitor of STAT3 from Ricinus communis, offering potential for therapeutic advancement in liver fibrosis treatment and drug development.