Binding interaction of Spilanthol and UDA with Malarial targets: Network pharmacology, ADME, Molecular docking, and Molecular dynamics simulation studies

Abstract

Worldwide, the escalating global malaria crisis driven by multidrug-resistant Plasmodium falciparum strains necessitates the urgent need for the development of anti-malarial drug. This study employs advanced computational methodologies to assess the anti-malarial properties of (2E,6Z,8E)-N-isobutyl-2,6,8-decatrienamide (Spilanthol) and (2E,4Z)-N-isobutyl-2,4-undecadiene-8,10-diynamide (UDA). Previous in vitro studies established their anti-malarial activity; however, this research integrates network pharmacology, molecular docking, ADME analysis, and molecular dynamics simulations to unravel their potential. Utilizing Swiss Target Prediction and Super-PRED databases, potential targets for Spilanthol and UDA were predicted, intersecting with malaria-related targets from Gene Cards and OMIM databases. Protein-protein interaction networks, visualized through STRING and Cytoscape 3.10.1, highlight common targets. Molecular docking reveals Spilanthol's robust binding affinity (-27.196 kJ•mol-1) to Prostaglandin G/H synthase 2 (PTGS2), indicating its promising anti-malarial candidacy. In drug development, ADMET properties play a pivotal role; therefore, SwissADME and AdmetSAR online servers were employed for In silico ADME and toxicity prediction. Molecular dynamics simulations further assessed the stability and conformational dynamics of the compounds. This comprehensive in-silico investigation enhances our understanding of Spilanthol and UDA's anti-malarial potential, providing valuable insights for potential clinical trials. These findings contribute to the ongoing efforts to combat malaria, emphasizing the importance of computational approaches in drug discovery and development.