title: Molecular simulation of a series of benzothiazole PI3Kα inhibitors: probing the relationship between structural features, anti-tumor potency and selectivity.
abstract: The phosphatidylinositol 3-kinase α (PI3Kα) was genetically validated as a promising therapeutic target for developing novel anticancer drugs. In order to explore the structure-activity correlation of benzothiazole series as inhibitors of PI3Kα, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) were performed on 61 promising molecules to build 3D-QSAR models based on both the ligand- and receptor-based methods. The best CoMFA and CoMSIA models had a cross-validated coefficient r(cv)(2) of 0.618 and 0.621, predicted correlation coefficient r(pred) (2) of 0.812 and 0.83, respectively, proving their high correlative and predictive abilities on both the training and test sets. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the ATP binding pocket. Based on the contour maps and MD results, some key structural factors responsible for the activity of this series of compounds were revealed as follows: (1) Ring-A has a strong preference for bulky hydrophobic or aromatic groups; (2) Electron-withdrawing groups at the para position of ring-B and hydrophilic substituents in ring-B region may benefit the potency; (3) A polar substituent like -NHSO(2)- between ring-A and ring-B can enhance the activity of the drug by providing hydrogen bonding interaction with the protein target. The satisfactory results obtained from this work strongly suggest that the developed 3D-QSAR models and the obtained PI3Kα inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and be helpful in future PI3Kα inhibitor design.
authors.affiliation: Center of Bioinformatics, Northwest A & F University, Yangling, Shaanxi 712100, China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Xiao
authors.forename: Guowen
authors.initials: G
authors.lastname: Sheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D056004:Molecular Dynamics Simulation; D058539:Phosphatidylinositol 3-Kinase / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D008024:Ligands; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase; C005465:benzothiazole