i have docked few molecules in to same receptor but could'nt judge which ligand is best...i just have just affinity (kcal/mol). is that enough? with that how can i judge the molecule. And also if i have two molecules of same affinity..what shd i do? I want them in reference to Discovery studio, MGL tools, Pymol and also how to do it also. Help will be deeply appreciated.
There is no one-stop answer to your question. The performance of docking programs and scoring functions can vary a lot, depending on the compound type and scoring function that Is used.
As often, the information you can collect about your target and its existing ligands will be key in getting the right compounds. If you know which interactions in your binding site are essential for activity, you can select your binding modes & ligands based on those criteria. For large number of compounds, this can rapidly get tricky however. Post-processing programs would be a must in that case.
Be careful about scoring functions. If you want to rely on them, you should at least validate them. Dock a number of known actives and see if your docking score correlates with activity. If it does not, check that the results of your scoring function at least provides decent enrichment when selecting active compounds from a set of decoy compounds. If it does not, why would you trust this function for selecting new ligands?
For the same reasons, do not blindly incorporate multiple scoring functions into a consensus score. If you incorporate scoring functions that perform badly, they will ruin your consensus score.
Last but not least... If you want to compare scores, try to use, for each compound, the scores of the most sensible binding mode (e.g. the binding mode where the correct interactions with the binding site were found). Again, post-processing programs can help greatly in this step.
A couple of things you may consider. First, after you chose a docking algorithm, you usually have a set of parameters as well as scoring functions that need to be adjusted. You can re-dock some known bounded molecules into your receptor to see what kind of docking algorithm in combination with docking parameters can best resemble the binding mode revealed in crystal or NMR experimental complex structure. Then you may consider use this docking method, parameters and scoring function to rank your candidates in future screening.
Secondly, after you get your docking result in screening, you can take advantage of a couple of different scoring functions to rank your candidates. I remembered Discovery studio can do this thing. Next, you may select the molecules that are always ranking high. You may resort to consensus score module in DS.
Lastly but perhaps most importantly, you are always suggested to turn back to papers to examine the detailed protein-ligand interactions. You can tell which molecule in the top list can best preserve these key interactions.
I hope these might be of some help.
The very best answer (but hard to make use of) is to start again and use a supercomputer with a good force field and calculate the free energy of binding by including very lengthy entropy calculations for protein, ligand, and solvent, and wait a vastly long time. Otherwise, your list is probably not very good anyway. In practice there may be some good suggestions about ranking drug etc. candidates in our paper Robson, B., Li, J., Dettinger, R., Peters, A., and Boyer, S.K. (2011), Drug discovery using very large numbers of patents. General strategy with extensive use of match and edit operations. Journal of Computer-Aided Molecular Design 25(5): 427-441 (2011) which I think I have a copy of to download on RG. See especially (but not solely) the Appendix which talks about the binding aspect.
You can also check the no. of hydrogen bonds formed using Ligplot and can also do the admet studies off the compound..
There is no one-stop answer to your question. The performance of docking programs and scoring functions can vary a lot, depending on the compound type and scoring function that Is used.
As often, the information you can collect about your target and its existing ligands will be key in getting the right compounds. If you know which interactions in your binding site are essential for activity, you can select your binding modes & ligands based on those criteria. For large number of compounds, this can rapidly get tricky however. Post-processing programs would be a must in that case.
Be careful about scoring functions. If you want to rely on them, you should at least validate them. Dock a number of known actives and see if your docking score correlates with activity. If it does not, check that the results of your scoring function at least provides decent enrichment when selecting active compounds from a set of decoy compounds. If it does not, why would you trust this function for selecting new ligands?
For the same reasons, do not blindly incorporate multiple scoring functions into a consensus score. If you incorporate scoring functions that perform badly, they will ruin your consensus score.
Last but not least... If you want to compare scores, try to use, for each compound, the scores of the most sensible binding mode (e.g. the binding mode where the correct interactions with the binding site were found). Again, post-processing programs can help greatly in this step.
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