Modeling Molecular Mechanisms of Pirfenidone Interaction with Kinases

Scar formation is a process that occurs due to increased collagen deposition and uncontrolled inflammation. Previous studies have demonstrated that Pirfenidone (Pf), an FDA approved anti-inflammatory and antifibrotic drug can reduce inflammation in vivo as well as regulate activation of LPS-stimulated neutrophils. However, the molecular level mechanism of Pf's action is not well understood. Here, we used neural networks to identify new targets and molecular modeling methods to investigate the Pf's action pathways at the molecular level that are related to its ability to reduce both the inflammatory and remodeling phases of the wound healing process. Out of all the potential targets identified, both molecular docking and molecular dynamics results suggest that Pf has a noteworthy binding preference towards the active conformation of the p38 mitogen activated protein kinase-14 (MAPK14) and it is potentially a type I inhibitor-like molecule. In addition to p38 MAPK (MAPK14), additional potential targets of Pf include AKT1, MAP3K4, MAP2K3, MAP2K6, MSK2, MAP2K2, ERK1, ERK2, and PDK1. We conclude that several proteins/kinases, rather than a single target, are involved in Pf's wound healing ability to regulate signaling, inflammation, and proliferation.