Application of the linear interaction energy method for rational design of artemisinin analogues as haeme polymerisation inhibitors

The anti-malarial activity of artemisinin-derived drugs appears to be mediated by an interaction of the drug's endoperoxide bridge with intra-parasitic haeme. The binding affinity of artemisinin analogues with haeme were computed using linear interaction energy with a surface generalised Born (LIE-SGB) continuum solvation model. Low levels of root mean square error (0.348 and 0.415 kcal/mol) as well as significant correlation coefficients (r ² = 0.868 and 0.892) between the experimental and predicted free energy of binding (FEB) based on molecular dynamics and hybrid Monte Carlo sampling techniques establish the SGB-LIE method as an efficient tool for generating more potent inhibitors of haeme polymerisation inhibition.