For the receptor-based pharmacophore generation, we generate hypothesis by utilizing the protein-ligand complex. However, if the ligand is forming a bond with the cofactor, then is it important to consider the cofactor in the generation of the hypothesis (receptor-ligand-cofactor)?
"Yes" seems like the obvious answer, unless your goal is to find ligands that bind to the target in the absence of the cofactor.
Indeed, it is important to consider the cofactor while generating the hypothesis, however, it seems practically impossible to generate receptor-based pharmacophore model along with co-factor. The better choice is to go with docking, where one can take account of the co-factor.
It depends on whether your want to dock your ligands to the co-factor or the substrate site. In the former case, the co-factor is supposed to be displaced by the ligand. However, the parts of the co-factor, which make key interactions with the enzyme can be used as pharmacophore features. However, if the ligand is docked to the substrate pocket, then the co-factor can be left in place and be considered as a part of the binding site. In the latter case, it would be able indeed to interact with the ligand.
Thank you, everyone, for your response.
In continuation of the above problem, I have few points to discuss like If we generate a receptor-based pharmacophore utilising the protein-ligand-cofactor, then it forms 6 or 7 feature pharmacophore hypothesis and on analysing the hypothesis, it seems that the software (Discovery Studio) is considering cofactor-ligand as one moiety (both are HET atoms). So the hypothesis that is obtained contain features from cofactor and ligand both.
Finally, can we use this hypothesis for virtual screening?
No, one cannot use such pharmacophore hypothesis for the virtual screening. As suggested by Prof. Dmitri Kireeve, you have to make it clear whether your want to dock your ligands to the co-factor or the substrate site.
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