Computational drug design for neurosyphilis disease by targeting Phosphoglycerate Kinase in Treponema pallidum with enhanced binding affinity and reduced toxicity.

Neurosyphilis, a severe neurological complication of syphilitic infection caused by the gram-negative spirochete Treponema pallidum poses significant challenges in treatment due to its irregular physiology and lack of efficacy in present therapeutic strategies. Here, we report a new approach to developing drug treatment that targets the enzyme phosphoglycerate kinase (PGK), an essential component of the T. pallidum glycolytic pathway. Therefore, a ligand was designed involving common neuroprotectant elements reported from literature by a computational drug design method, to increase their binding energy with lower toxicity. The calculated binding affinity of the designed ligand with PGK was analyzed by molecular docking to be - 116.68 kcal/mol. Also, interaction analysis predicted that there are 5 hydrophobic bonds and 3 hydrogen bonds present between the docked complex. Afterward, in-silico ADMET studies were conducted for the designed ligand that determined a strong pharmacological profile with good absorption, zero violation of Lipinski's rule, and non-toxic properties. DFT analysis further optimized the ligand with a HOMO/LOMO gap value of 0.01421 kcal/mol indicating higher reactivity and enhanced electronic interactions, improving ligand efficiency. Moreover, pharmacophore modeling confirmed the reactive nature of the ligand. Furthermore, MD simulations showed stability in the overall structure. The output shows that our optimized ligand has statistically better binding affinity than the currently used drug penicillin, with improved pharmacokinetic profiles. This work demonstrates the importance of ligand design for the discovery of new drugs to treat neurosyphilis.