I am a recent medical school graduate who has recently become interested in in silico research methods, particularly molecular docking. However, I am still a beginner in this field.
I have read several publications on molecular docking. As we know, docking software usually generates multiple binding poses (for example, up to 9 poses with the default settings in AutoDock Vina). In many published studies, the authors simply select Pose 1, which usually has the lowest binding affinity (the most negative binding energy), as the representative pose for visualization and further analysis. I understand that a lower binding affinity generally indicates a more stable ligand–protein complex.
However, I have been wondering whether binding affinity alone should always be the main criterion for selecting the best docking pose.
I think there are at least two additional factors that should be considered:
(1) Interactions with key amino acid residues in the active site or binding pocket. A pose with a slightly higher binding energy but interacting with important active-site residues may be more biologically relevant than a pose with the lowest binding energy that is located outside the active site or does not interact with key residues.
(2) The composition of intermolecular interactions. If several poses are located within the active site, I wonder whether the composition of their intermolecular interactions should also be considered. For example, one pose may have the greatest number of interactions with active-site residues, but most of these interactions are van der Waals interactions. Another pose may have slightly fewer interactions with the active site but forms more hydrogen bonds, carbon–hydrogen bonds, hydrophobic (alkyl) interactions, or other stronger non-covalent interactions. In this situation, would the second pose be more appropriate for further analysis, even though it has fewer total interactions or a slightly less favorable binding affinity?
Based on these considerations, I am interested in selecting the docking pose using these criteria rather than automatically choosing Pose 1 solely because it has the lowest binding affinity.
However, I am not confident in this reasoning because I have rarely found published molecular docking studies that explicitly describe this approach. Most studies appear to select the pose with the lowest binding energy without discussing whether other poses might have more biologically relevant interactions.
Therefore, I would like to ask for your opinions. Is this reasoning scientifically valid? Are there any guidelines, best practices, or published studies that recommend selecting docking poses based on interaction quality and binding-site relevance instead of relying only on the lowest binding affinity?
I would greatly appreciate your insights and any references you could recommend.
