Targeting neuraminidase a of Multidrug-Resistant Streptococcus Pneumoniae: Virtual screening, docking, and redesigning of traditional Chinese Medicine Compounds

Abstract

Streptococcus pneumoniae infections cause high mortality and morbidity around the world due to rapidly increasing antibiotic resistance. Thus, there is a need for new and more effective drugs. 3D models of neuraminidase A (NanA), a potential target of MDR pneumococcal strains CGSP14 and Canada 19F, were generated via homology modeling with the wild type TIGR4 NanA as template. Potential lead compounds in the TCMSP database were then screened by docking to the generated models. The identified compounds were scored and ranked according to biding energy and compliance with Lipinski’s rule of five. The top-ranking ligands were then redesigned and through fragment-based drug design and then redocked to the generated models. The redesigned ligands were scored and ranked according to binding energies, Lipinski’s rules, polar surface area, and solubility. The molecular interactions of the ligands with the active site were also analyzed. Out of the 6,699 TCMSP compounds docked, there were 132 hits for CGSP14 NanA and 134 hits for Canada19F NanA. The top-ranking compounds for CGSP14 are MOL002656, MOL003942, MOL003959, and MOL6393; and for Canada19F, MOL002659, MOL011100, and MOL011098. Redesigning of the top-biding compounds resulted in eight novel ligands for CGSP14 and four for Canada19F. The most drug-like redesigned ligands were designated D3959x791 and D3959x11098 for CGSP14, and D2587c3207 and D6411x6877 for Canada19F. The redesigned ligands may be used for in vivo and in vitro studies against S. pneumonia. Further, the top-ranking TCM compounds identified may be refined and formulated for drug manufacturing.