Lignan derivatives potential as Plasmodium falciparum Lactate Dehydrogenase inhibitors: Molecular docking approach of antiplasmodial drug design

Objectives: To investigate the lignan derivatives potential as Plasmodium falciparum Lactate Dehydrogenase (PfLDH) inhibitors by using Computer Aided Drug Design (CADD) and molecular docking approach. Methods: In finding potential antiplasmodial, in silico approach has been utilized. Protein structure of PfLDH has been built through homology modeling. Kobamin has been used to refine the 3D PfLDH structure. Structure validation of PfLDH was done by Ramachandran Plot and ERRAT calculations. The validated PfLDH was ready for molecular docking analysis. lignan derivatives as lead compounds were designed. The pharmacophore of lignan derivatives were assessed by using Molsoft drug likeness. Both protein and Lignan derivatives were docked with Autodock Vina. The best docking score was shown by the lowest affinity energy. Results: Homology modeling of PfLDH has been built. Moreover, PfLDH refinement and validation were importantly conducted to ensure that PfLDH structure was in good quality. According to Ramachandran Plot and Procheck analysis, PfLDH has good structure quality with 93.39% confidence value. On the other hand, lignan derivatives assessment also has been done by evaluating their physicochemical and pharmacophore properties as lead compounds. From this assessment, it showed that Aristoligol (ARG1), Aristoligone (ARG2), and Ester Asetil Aristoligol (ARG3) showed good compounds to be drug likeness by following Lipinski’s rule of five (RO5), while Ester Butiril Aristoligol (ARG4) showed poor RO5 criteria. Bioavailability of four compounds was good in body metabolism, however, ARG3 and ARG4 could not be lead like compounds due to poor lead likeness value. From molecular docking result, the most favorable binding with PfLDH was ARG4 based on its affinity energy value (-8.0 kj/mol), followed by ARG3, ARG2 and ARG1, respectively. Conclusions: The identification of potential anti plasmodial drugs was successfully accomplished by evaluating synthetic lignan derivatives compound through physicochemical properties and molecular docking analysis. Overall, physicochemical and pharmacophore properties showed good result. Molecular docking interaction has distinct mode interactions of lignan derivatives with PfLDH. We believe that these evaluated compounds could be used as anti plasmodial drugs according to in silico evaluation results.