Identification novel peptides conjugated to hiv1 tat peptide to inhibit ebola virus entry by targeting niemann pick C1 protein

Ebola virus (EBOV) is the causative agent of Ebola hemorrhagic fever. Currently, there is no effective drug to treat EBOV infection. Niemann Pick C1 (NPC1) is one of the proteins involved in cholesterol homeostasis which emerge as an essential protein in EBOV entry process into the cell. In this research, a series of pharmacophore-based virtual screening and molecular docking simulations were performed to investigate the most potent peptide conjugated to HIV1 Tat peptide as a drug candidate inhibiting NPC1 protein. About 47,512 peptide compounds from NCBI PubChem database, which selected as ligands inhibitor, were screened to eliminate undesired properties. Then, about 12,863 peptides underwent virtual screening, rigid docking, and flexible docking simulations to obtain ligands with favorable inhibition activities. Nine selected ligands with lower Gibbs free binding energy value compared to standard ligand were conjugated to HIV1 Tat peptide to accumulate them inside the endosome, and the inhibition activity was recalculated by flexible docking simulation. Only three ligands, Alarelin, Neurokinin beta, and Callitachykinin I displayed better affinity and minimal conformation changes in the interaction compared to its unconjugated ligand. Then, the potential ligands underwent ADMETox prediction by using AdmetSAR, Toxtree, DataWarrior, and pkSCM software. Three ligands c-callitachykinin, c-neurokinin beta, and c-alarelin showed favorable characteristics as a new drug candidate for the NPC1 inhibitor according to the interaction of the amino acid residues, RMSD, and Gibbs free binding energy.