Consensus model for identification of novel PI3K inhibitors in large chemical library.
Phosphoinositide 3-kinases (PI3Ks) inhibitors have treatment potential for cancer, diabetes, cardiovascular disease, chronic inflammation and asthma. A consensus model consisting of three base classifiers (AODE, kNN, and SVM) trained with 1,283 positive compounds (PI3K inhibitors), 16 negative compounds (PI3K non-inhibitors) and 64,078 generated putative negatives was developed for predicting compounds with PI3K inhibitory activity of IC(50) < or = 10 microM. The consensus model has an estimated false positive rate of 0.75%. Nine novel potential inhibitors were identified using the consensus model and several of these contain structural features that are consistent with those found to be important for PI3K inhibitory activities. An advantage of the current model is that it does not require knowledge of 3D structural information of the various PI3K isoforms, which is not readily available for all isoforms.
Pharmaceutical Data Exploration Laboratory, Department of Pharmacy, National University of Singapore, Singapore, Singapore.
Chin Yee
CY
Liew
Xiao Hua
XH
Ma
Chun Wei
CW
Yap
D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054852:Small Molecule Libraries