Question

I am carrying out a virtual screening project for a protein receptor to identify possible ligands (small molecules). After the virtual screening, molecular dynamics, and MMGBSA calculation, I identified two ligands that differ only by one carbonyl group. Because this has not been published, I cannot disclose the structure. The MD study shows that the ligand without the carbonyl group is more stable over time (0-100ns). And MMGBSA calculation also shows that the one without the carbonyl group binds better.

From my understanding, having a carbonyl group should increase the likelihood of interacting with amino acids, and thus contributing to binding. I appreciate it if anyone could offer some possible reasons why this is the case (no carbonyl group is better). I asked GPT and it tells me it might be the steric effect which makes sense. Are there any further analyses I can do to answer this question?

By the way, I meant it to be a fully computational study, and thus I do not plan to validate it by wet lab.

Answer 1

The presence of a carbonyl group in a ligand may lead to better binding potential through hydrogen bonding, yet it can also introduce steric hindrance or unfavorable energetics, which explains why a ligand without it may bind better.

Step-by-step explanation:

In computational chemistry, the absence of a carbonyl group in a ligand leading to better binding and stability in a protein-ligand complex can arise from several factors. Although a carbonyl group can indeed form interactions such as hydrogen bonds with amino acids within the protein, its presence might also introduce steric hindrance or lead to an unfavorable energetic environment, negating its beneficial effects. Furthermore, the carbonyl group may result in a suboptimal conformation or alignment with respect to the active site that prevents other, potentially stronger, interactions from occurring.

To further analyze this phenomenon, you might consider examining the protein-ligand docking results more closely, perhaps looking at the conformational changes upon ligand binding. Another approach could be to analyze the changes in the solvent-accessible surface area upon ligand binding, which could provide insight into the ligand's interactions with the protein's exterior and surrounding water molecules. Additionally, you can investigate the structure-activity relationship (SAR) by comparing the effects of the presence and absence of the carbonyl group on the biological activity. This might include observing the electrostatic potential maps to understand electron distributions that affect binding affinities.