The Virtual Screening Of CRM1 Inhibitors Based On PubChem Database And The Application For Acne Treatment

Small molecule covalent inhibitors are a kind of inhibitors which form a covalent bond with target protein and subsequently play a biological function in organism. As one of nuclear protein B family, CRM1 is a ubiquitous transporter receptor protein. CRM1 has a hydrophobic nuclear export signal peptide sequence Φ1-X2.3-Φ2-X2,3-Φ3-XΦ4, which can combine with the cargo and transport them from the nucleus to the cytoplasm. The inhibitors of CRM1 can inhibit the transport capacity of Cys528 by the Michael addition reaction. In most cases the combination is irreversible. Computer aided drug design is a new technology that is used in the design and optimization of molecular drug. It combines a variety of subjects such as computational chemistry and molecular pharmacology and simulates binding process between ligand and receptor by using some programs on computer. The technology can shorten the period of drug design greatly and reduce the cost at the same time. Acne is a kind of skin disease which often occur in the face. Because of the processes of treatment need many repeats, the disease distresses a large part of adolescent patients. Therefore, the design and use of natural covalent inhibitors becomes particularly important in term of targeting CRM1 protein to treat acne.In our study, we conducted a virtual screening of a pharmacophore in PubChem database. What’s more, we conducted molecular docking between CRM1 and the structures which contain the pharmacophore by AutoDock Tools software. Then, we conducted molecular dynamics simulations of Parthenolide and Tripolide by Gromacs and other molecular dynamics simulation software. Finally, we extract some components of papaya seeds and apply them to the rabbit ear model of acne.Through the above experiment, we obtain the conclusion as follows:(1) In all provided PubChem database, there are 86 database containing the structure of the pharmacophore and the total is 334.(2) After docking, we select ten structures whose score are highest for further analysis. What’s more, we compare the interaction of the ten structures and Leptomycin B with CRM1-NES pocket. The results show that the ten structures are potential inhibitors.(3) Molecular dynamics simulations indicate the binding modes of Parthenolide and Triptolide are similar to the binding mode of Leptomycin B. Furthermore, the interaction of CRM1/Triptolide is significantly better than CRM1/Parthenolide, and the activity can be verified by experiments.(4) Papaya seed extract can treat acne effectively.