oa In silico design of selective high affinity ligands to block CD81-Plasmodium falciparum sporozoites interaction

Background and Objectives: Around one million deaths result from malaria each year worldwide. The infection starts by the inoculation of sporozoites by female Anopheles mosquito into the host. The mechanism of invasion of sporozoites into the host is not clear to date. CD81 is considered the only host receptor to be significant for the invasion of sporozoites. The aim of the first phase of this project is to identify potential ligands that binds with high affinity to the residues in CD81 involved in CD81-malaria sporozoites interaction in silico, use them to generate selective high affinity ligands (SHALs) and use these SHALs to inhibit the interaction of CD81-sporozoites, thus preventing progression of malaria infection. Methods and Results: AutoDockTools 1.5.6 was used to prepare the crystal structures of the CD81-LEL protein (1G8Q) by deleting water molecules, adding polar hydrogens, and assigning Gasteiger charges and to create a grid bounding box, which provided the desired grid parameter file using 0.375 A spacing. Autoligand, an AutoDock tool, was used to identify several binding sites on CD81. Fill points were created using a 1 A grid, and the calculations were performed using 10 to 210 fill points. AutoDock 4.2 was used to screen 30,000 ligands obtained from different libraries (NCI_DSII and Asinex) to identify small molecules that might bind to each site. The docking results were analyzed and virtual screening hits for each binding site on CD81-LEL were ranked according to selection criteria required for the design of promising SHALs. Distances between pairs of bound ligands were estimated and used to design several SHALs that should bind selectively to CD81. Conclusion: New computational tools have been used to design in silico several SHAL-based inhibitors that have the potential to prevent entry of Plasmodium falciparum sporozoites into hepatocytes and thus malaria infection.