Discovery of the Specific Inhibitory Effect of Thiamphenicol on LPS-induced Acute Lung Injury (ALI) in Mice Through Virtual Screening and Biological Evaluation

A B S T R A C T Acute lung injury (ALI) is an acute and persistent pulmonary inflammatory syndrome. Neutrophil elastase (NE) activity is increased during ALI to regulate lung inflammation and hydrolyze a variety of matrix proteins that subsequently cause lung injury. Small molecule compounds with pyrrolidine trans-lactam structure can bind NE and inhibit its activity, improving the symptoms of ALI in model animals. Based on this information, we conducted virtual screening of small molecule compounds with pyrrolidine trans- lactam structures that may have NE inhibitory activity in the compound libraries and combined with in-depth screening and molecular docking validation, the compound thiamphenicol (TAP) with potential NE inhibitory activity was finally obtained. In vivo experiments in mice with ALI showed that TAP could significantly reduce LPS-induced pulmonary edema, decrease microvascular permeability, improve pathological and ultrapathological damage in lung tissue, and maintain the normal structure and function of the alveolar-capillary endothelial barrier. It could also improve the degradation of vascular endothelialcadherin (VE-cad). Pharmacological mechanism tests also demonstrated that TAP significantly inhibited NE activity in lung tissue of LPS-induced ALI mice, but did not affect the expression of NE protein. In addition, the application of TAP did not cause side effects of glucocorticoids in the conventional clinical treatment of ALI. We believe that this paper could provide a new structure for drugs used in the treatment of ALI, which will certainly contribute to the development of new chemical structures as drugs for the treatment of ALI.(c) 2022 Elsevier B.V. All rights reserved.