Targeting Neuraminidase A of Multidrug-Resistant Streptococcus pneumoniae: Molecular Docking and Redesign of Traditional Chinese Medicine Compounds

Streptococcus pneumoniae infections cause high mortality and morbidity worldwide due to the rapidly increasing antibiotic resistance of the said pathogen. The role of neuraminidase A (NanA) enzyme in the colonization and biofilm formation of S. pneumoniae makes it a promising target for drug design. 3D models of multidrug-resistant pneumococcal strains CGSP14 and Canada19F were generated via homology modeling with the wild type TIGR4 NanA as template. A total of 6,699 compounds from the Traditional Chinese Medicine Systems Pharmacology database were screened by docking to the models. The top high-affinity compounds were redesigned by combining them and then were redocked to the generated models. The redesigned ligands were scored and ranked according to binding energy, Lipinski’s rules, polar surface area, and solubility. The molecular interactions of the ligands with the active site were analyzed. The top-ranking redesigned ligands are D6393x1351 for CGSP14 and D2585x3207 for Canada19F, which had binding affinities less than or equal to -9.0 kcal/mol, and drug-like physicochemical properties. Testing of the redesigned ligands in in vivo and in vitro ADMET studies as possible candidates for drug development against S. pneumoniae is recommended.