Structure-Based Virtual Screening, ADMET Properties Prediction and Molecular Dynamics Studies Reveal Potential Inhibitors of Mycoplasma pneumoniae HPrK/P.

Mycoplasma pneumoniae pneumonia (MPP) is a frequent cause of community-acquired pneumonia (CAP) in children. The incidence of childhood pneumonia caused by M. pneumoniae infection has been rapidly increasing worldwide. M. pneumoniae is naturally resistant to beta-lactam antibiotics due to its lack of a cell wall. Macrolides and related antibiotics are considered the optimal drugs for treating M. pneumoniae infection. However, clinical resistance to macrolides has become a global concern in recent years. Therefore, it is imperative to urgently identify new targets and develop new anti- M. pneumoniae drugs to treat MMP. Previous studies have shown that deficiencies in HPrK/P kinase or phosphorylase activity can seriously affect carbon metabolism, growth, morphology, and other cellular functions of M. pneumoniae . To identify potential drug development targets against M. pneumoniae , this study analyzed the sequence homology and 3D structure alignment of M. pneumoniae HPrK/P. Through sequence and structure analysis, we found that HPrK/P lacks homologous proteins in the human, while its functional motifs are highly conserved in bacteria. This renders it a promising candidate for drug development. Structure-based virtual screening was then used to discover potential inhibitors among 2614 FDA-approved drugs and 948 bioactive small molecules for M. pneumoniae HPrK/P. Finally, we identified three candidate drugs (Folic acid, Protokylol and Gluconolactone) as potential HPrK/P inhibitors through molecular docking, molecular dynamics (MDs) simulations, and ADMET predictions. These drugs offer new strategies for the treatment of MPP.