Attached paper is helpful in discussing reliability of docking results. Are the IC50 values are for an enzyme inhibition assay for the target enzyme used in docking or cellular assays using cell lines in which the target enzyme are overexpressed in ?

Thank you Mr. Gabr for your fast reply.

In fact, the IC50 values are for an enzyme inhibition assay for the target enzyme used in docking, where the top scoring compound showed a relatively lower IC50 compared with another analog with better in vitro activity and less docking score.

The purpose of molecular docking is to obtain reasonable models of protein-ligand complexes for which no experimental structure is available. Docking scores cannot be directly compared with experimental IC50 values or binding free energies.

If you understand how IC50 is calculated and what exactly it means, and how docking scores are calculated and what they mean, you wouldn't even expect docking scores to correlate with IC50! One relates to calculated binding energies while the other is an estimate of concentration of compound that inhibits 50% of protein activity. Where is the common ground?!!!

It is not possible to get 1 to 1 correlation in between docking score and IC50 value. One is based on algorithms and scoring function (theory) and other one is experimental. Docking gives you the value with which the ligand gets bind with the protein and IC50 gives you the value responsible for inhibition. Docking can not predict if the binding ligand is inhibiting the enzyme function.

The reasons for the unmatching between docking scores and IC50 values might be: 1) wrong binding site and/or pose prediction, 2) incorrect protein and/or ligand representation (flexibility, missing structural information like loops or interaction partners, solvation, protonation, tautomerism, isomerism), 3) non-optimal docking program and/or setup for a current case, 4) imperfection of the docking scores (e. g., desolvation effects and entropy are quite problematic), 5) poor experimental data (for example, when collecting IC50 values from different sources), 6) unsuitable mathematical form of IC50 (usually conversion to the logarithmic form is required if a linear correlation with the docking score is expected). I guess this list is not full.. Major challenges of docking are nicely discussed in this review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996748/ I hope my answer was helpful.

Perhaps this recent publication could be helpful:

Molecular Docking and Structure Activity Relationship Studies of NSAIDs. What do they Reveal about IC50?,Letters in Drug Design & Discovery,

14, 8,  949-958, 2017, doi:10.2174/1570180814666161207143231,

http://www.eurekaselect.com/node/148175/article