In Silico Screening and Redesigning of Traditional Chinese Medicinal Compounds Against Neisseria gonorrhoeae Aspartate-Semialdehyde Dehydrogenase (ASADH) and 4-Hydroxy-Tetrahydrodipicolinate (HTPA) Reductase

Abstract

Neisseria gonorrheae is the primary causative agent of gonorrhea, the second most common sexually transmitted infection worldwide. Aspartate-semialdehyde dehydrogenase (ASADH) and 4-hydroxy-tetrahydrodipicolinate (HTPA) reductase, enzymes involved in the lysine biosynthetic pathway, are promising targets against this pathogen. Homology and structure analyses of target enzymes were done. 6,699 curated molecules from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database were docked with each enzyme. The top hit for ASADH_mod was MOL004016 with a binding free energy (∆G) of -9.895 kcal/mol. For HTPA reductase_mod, MOL000893 had the lowest binding free energy (∆G) of -10.880 kcal/mol. Nineteen out of the top 20 ligands from the TCMSP database for ASADH_mod and HTPA reductase_mod satisfy Lipinki’s Rule of Five. Ligands were redesigned to create compounds with enhanced binding affinities to the enzymes. The top three redesigned ligands docked to ASADH_mod are R1A (MOL008461x011100x011124_13), R2A (MOL008461x011100x011124_3), and R3A (MOL008461x011100x011124_7) with binding free energies ((∆G) of -9.542, -10.080, and -10.040 kcal/mol, respectively. The top three redesigned ligands docked to HTPA reductase_mod are R1B (MOL004016x006873_1+, R2B (MOL000893x 002659_8), and R3B (MOL000893 v002659_3) with binding free energies (∆G) of -11.290, -12.230, and -11.470 kcal/mol, respectively. All top redesigned ligands docked with each enzyme satisfy Lipinski’s Rule of Five. For each enzyme, there is one soluble and two moderately soluble top redesigned ligands. All redesigned ligands are predicted to be highly absorbed by the gastrointestinal tract. The to hits and redesigned ligands hold promose for drug development against N. gonorrheae.