Are structure-based peptide drug design and ligand-based peptide drug design mutually exclusive? If we have the crystal structure of the protease and design the peptide inhibitor based on the sequence of its ligand (protease cleavage site), is it a structure-based peptide drug design and ligand-based peptide drug design or a hybrid of both? Thank you.
I think this depends. If you design a peptide inhibitor based on a sequence of protease ligand using qsar or a ligand-based pharmacophore method, that is a ligand-based drug design. And if you design a peptide inhibitor based on the sequence of protease ligand and then study the interaction of the designed substance with the target by molecular docking or molecular dynamics simulation to be able to further optimize the structure, that is the combination of structure- and ligand-based drug design. Also, I think hybrid method of both should be understood as a combination of two methods.
SBDD refers to the design of the molecule based on the known 3D structure of a protein target binding site. If you however design molecule based on the structure on a known ligand for some protein target (usually in the absence of 3D protein structure or a model) then it is LBDD. They do not have to be mutually exclusive though, you can combine the methodologies, when you know the structures of both protein target and native substrate, ligand or drug that binds to the target protein.
Thank you for your answers. I got the crystal structures of my protein and peptide from pdb. At the same time, I mutated the binding loop of the peptide with the sequence of the protease cleavage site. So, the wild-type peptide was basically the scaffold for peptide design. This should be considered as the hybrid of structure-based drug design and ligand-based drug design. Am I right?
I think yes. Here is one recent publication on that matter:
Molecules 2020, 25, 4723; doi:10.3390/molecules25204723
Structure-based can be divided into the holo-structure and apo structure. Holo-structure is the condition of the ligand with protein, apo-structure is the prediction in an empty binding site. Apo-structure prediction is full of uncertainty, for apo-prediction, it is better to find a known inhibitor then do the docking to predict the important residues. For ligand-based, you can try to do a literature review for the target protein and find the similarities between them or you can check the ligand available at the ChemBL database. Hope this can help you
Thank you, Helmi Husaini Zainal Fithri , Philippe Roger Bovy and Ivana Jevtic
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