A De-Novo drug design and ADMET study to design small molecule stabilisers targeting mutant (V210I) human prion protein against familial Creutzfeldt-Jakob disease (fCJD)

Abstract

The purpose of our project was to computationally design small molecule stabilisers targeting mutant (V210I) human prion protein (HuPrP) using combined De-novo pharmacophore based drug design and virtual molecular docking. The newly designed molecules were also analysed so it might qualify as a new cure for the familial Creutzfeldt-Jakob disease (fCJD). We collected the target protein structure from protein data bank (RCSB PDB). and minimised the energy using Yasara energy minimisation webserver and validated the structure using RAMPAGE webserver. We used KV Finder, a plug-in of Pymol to identify the drug binding pockets in the target protein. The pocket information was used for de-novo ligand design using the e-LEA3D webserver. Those ligands were used to generate a pharmacophore using LigandScout for the selected pockets. The pharmacophores were used as the search templates using Pharmit for the virtual screening of small molecules from Pubchem database followed by the docking of the screened small molecules in the pockets using Autodock Vina. Best five molecules were selected for ADMET properties using SwissADME. All the five small molecules were proven to be the ideal candidates for further drug development.