Discovery of novel antimalarial drugs based on thiosemicarbazone derivatives: An in silico approach

Abstract

Thiosemicarbazones belongs to the group of semicarbazides which contains sulfur atom instead of the oxygen atom. Several studies have shown that they are effective against extracellular protozoans like Trichomonas vaginalis, Plasmodium falciparum, Trypanosoma cruzi and other parasites. The current research involves pharmacophore model design, 3-D-QSAR, virtual screening, and docking studies, all of which are evaluated using various parameters. The present study was performed by Schrodinger software. A total of 40 ligands were selected for the development of 3D QSAR models. To predict the pIC50 values in 3D-QSAR analysis, the entire dataset was divided into two sets, training and test sets, in a 7:3 ratio. The selected pharmacophore hypothesis has been selected for the virtual screening study. DHHRR_1 emerged as the best pharmacophore model with a survival score of 5.80. The 3D QSAR study showed a significant model with R2 =0.91 and. Q2 = 0.73. The series top-scoring compound 7e had a docking score of -10.44 and showed interactions with the amino acids ARG-265, PHE-227, and LEU-531 required for activity. The developed pharmacophore model has been used for screening of ZINC compounds where ZINC26244107, ZINC13469100, ZINC01290725and ZINC01350173 showed thebest XP docking scores (-11.60, -11.27, -11.35, -10.52, consecutively) with binding important amino acids ARG265, HIE185 and LEU 531 against plasmodium falciparum, PDB ID: 5TBO. These results wereevaluated with thestandard antimalarial drug chloroquine. ADME analysis showed the drug-likeness properties of the compounds. The results of the present study may be helpful for the future development of antimalarial compounds against Plasmodium falciparum.