Computational methods have been used to design a new drug that might be used to target the defective protein present in familial Creutzfeldt-Jakob disease (fCJD). The de novo pharmacophore-based drug design and virtual molecular docking work is described in detail in the International Journal of Computational Biology and Drug Design.
To create their designer drug, the team starts with a data file that describes the complete structure of the target protein obtained from the Protein Data Bank (RCSB PDB). They use a computational model, the Yasara energy minimisation webserver to drill down on this structure to obtain its likely shape and form in the body. This minimized structure is then validated using the RAMPAGE webserver.
The next step is to use yet more computational tools to home in on hollows or “pockets” in the protein structure into which putative small molecule drugs might fit, or dock. With those pockets in hand, they then use another tool to generate likely chemical structures that might fit, this ultimately gives them an optimal “pharmacophore”, a plausible drug structure, which can be used as a template to search the PubChem database of known chemicals that have a very similar size and shape. The team then uses a docking program to see which of those chemicals in the database are most likely to fit the pockets in the target protein in this disease.
They identified five small molecules that might be active in this context. Analysis of these chemicals’ ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties show that any of the five might ultimately be proven to be candidates for further investigation in the laboratory and ultimately in the clinic as drug development leads.
The team says that their approach could be helpful in the design and development of many more potential anti-prion drugs. Optimising the method to incorporate more sophisticated modeling techniques could improve the drug leads obtained.
Alam, R., Rahman, G.M.S., Hasan, N. and Chowdhury, A.S. (2020) ‘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)’, Int. J. Computational Biology and Drug Design, Vol. 13, No. 1, pp.21–35.
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