Application of orthogonal L-shaped PLS to chemogenomic data and its chemical interpretation from predictive and orthogonal latent variables

• The application of L-shaped PLS (LPLS) method has been reported from our group.
• We used orthogonal LPLS (OLPLS) and tried a validation study for chemogenomic data.
• We selected adenosine inhibitory activity data as chemogenomic data.
• We successfully elucidated the predictive and orthogonal fragments on a ligand structure.

We carried out a validation study of the orthogonal L-shaped PLS (OLPLS) method using chemogenomic data based on adenosine receptor inhibitor activity measurements. Using OLPLS, the ligand and protein descriptors could be connected to eight adenosine receptor inhibitor activities. The fingerprints representing specific chemical substructures on the ligands were used as the ligand descriptors, while z-scales were used as the protein descriptors. Three clusters were observed in the chemical and protein spaces from the predictive scores and loadings. From these, the predictive and orthogonal ligand structure fragments towards three adenosine receptors could be successfully elucidated. The predictive fragment for the human adenosine 2A receptor was confirmed by comparison to the X-ray crystal structure. As expected, the orthogonal fragments contained no physicochemical features required for specific interaction with the adenosine receptors.