Identifying Bioactive Conformations of Flexible Polyunsaturated Fatty Acids for Ligand-Based Drug Design

Polyunsaturated fatty acids (PUFAs) are signaling molecules exhibiting diverse bioactivities. Due to their flexible nature, PUFAs can theoretically adopt an enormous number of conformations, and it is not easy to identify the biologically active conformation(s), so rational drug design targeting the corresponding receptors is difficult. Here, we established a method to characterize conformational similarity by combining the replica exchange molecular dynamics simulation with the 3-dimensional WHIM (Weighted Holistic Invariant Molecular) descriptor. Using this method, we explored the total conformational space of 6 PUFAs and identified their conformational preferences for binding to known proteins. We found that upon binding, a specific cluster of conformers from the solution state is populated, which can be termed as bioactive conformations. By comparing the dynamics of synthetic modulators with those of PUFAs, we found that these compounds can be regarded as rigid mimics of the bioactive conformations of PUFAs, though this perspective has not been previously described. This approach is expected to be helpful in designing new bioactive molecules.