Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions

PLoS One. 2024 Jun 26;19(6):e0302390. doi: 10.1371/journal.pone.0302390. eCollection 2024.

Abstract

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.

MeSH terms

  • Animals
  • Drug Design*
  • Humans
  • Ligands
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Multienzyme Complexes
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors
  • NADH, NADPH Oxidoreductases / chemistry
  • NADH, NADPH Oxidoreductases / metabolism
  • Quantitative Structure-Activity Relationship*
  • Schistosoma mansoni* / drug effects
  • Schistosomiasis* / drug therapy

Substances

  • Ligands
  • thioredoxin glutathione reductase
  • NADH, NADPH Oxidoreductases
  • Multienzyme Complexes

Grants and funding

The author(s) received no specific funding for this work.