Predicting Subtype Selectivity for Adenosine Receptor Ligands with Three-Dimensional Biologically Relevant Spectrum (BRS-3D).
Adenosine receptors (ARs) are potential therapeutic targets for Parkinson's disease, diabetes, pain, stroke and cancers. Prediction of subtype selectivity is therefore important from both therapeutic and mechanistic perspectives. In this paper, we introduced a shape similarity profile as molecular descriptor, namely three-dimensional biologically relevant spectrum (BRS-3D), for AR selectivity prediction. Pairwise regression and discrimination models were built with the support vector machine methods. The average determination coefficient (r2) of the regression models was 0.664 (for test sets). The 2B-3 (A2Bvs A3) model performed best with q2= 0.769 for training sets (10-fold cross-validation), and r2= 0.766, RMSE = 0.828 for test sets. The models' robustness and stability were validated with 100 times resampling and 500 times Y-randomization. We compared the performance of BRS-3D with 3D descriptors calculated by MOE. BRS-3D performed as good as, or better than, MOE 3D descriptors. The performances of the discrimination models were also encouraging, with average accuracy (ACC) 0.912 and MCC 0.792 (test set). The 2A-3 (A2Avs A3) selectivity discrimination model (ACC = 0.882 and MCC = 0.715 for test set) outperformed an earlier reported one (ACC = 0.784). These results demonstrated that, through multiple conformation encoding, BRS-3D can be used as an effective molecular descriptor for AR subtype selectivity prediction.
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.|College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
Song-Bing
SB
He
Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
Ben Hu
Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
Zheng-Kun
ZK
Kuang
College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
Dong
D
Wang
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.|Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
De-Xin
DX
Kong
D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D060388:Support Vector Machine
D008024:Ligands; D018047:Receptors, Purinergic P1