Azolium analogues as CDK4 inhibitors: Pharmacophore modeling, 3D QSAR study and new lead drug discovery

• Published in: Journal of molecular structure Vol. 1134; pp. 482 - 491
• Main Authors: Rondla, Rohini, Padma Rao, Lavanya Souda, Ramatenki, Vishwanath, Vadija, Rajender, Mukkera, Thirupathi, Potlapally, Sarita Rajender, Vuruputuri, Uma
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.04.2017
• Subjects: 3D QSAR model; ADME analysis; Azolium analogues; CDK4 inhibitors; Lead drug discovery; Pharmacophore mapping; Lead drug discovery; CDK4 inhibitors; Pharmacophore mapping; 3D QSAR model; ADME analysis; Azolium analogues
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2016.12.106

The cyclin-dependent kinase 4 (CDK4) enzyme is a key regulator in cell cycle G1 phase progression. It is often overexpressed in variety of cancer cells, which makes it an attractive therapeutic target for cancer treatment. A number of chemical scaffolds have been reported as CDK4 inhibitors in the literature, and in particular azolium scaffolds as potential inhibitors. Here, a ligand based pharmacophore modeling and an atom based 3D-QSAR analyses for a series of azolium based CDK4 inhibitors are presented. A five point pharmacophore hypothesis, i.e. APRRR with one H-bond acceptor (A), one positive cationic feature (P) and three ring aromatic sites (R) is developed, which yielded an atom based 3D-QSAR model that shows an excellent correlation coefficient value- R2 = 0.93, fisher ratio- F = 207, along with good predictive ability- Q2 = 0.79, and Pearson R value = 0.89. The visual inspection of the 3D-QSAR model, with the most active and the least active ligands, demonstrates the favorable and unfavorable structural regions for the activity towards CDK4. The roles of positively charged nitrogen, the steric effect, ligand flexibility, and the substituents on the activity are in good agreement with the previously reported experimental results. The generated 3D QSAR model is further applied as query for a 3D database screening, which identifies 23 lead drug candidates with good predicted activities and diverse scaffolds. The ADME analysis reveals that, the pharmacokinetic parameters of all the identified new leads are within the acceptable range. [Display omitted] •Ligand based pharmacophore model is generated to specify the essential structural features of CDK4 inhibitors.•An atom based 3D-QSAR model with good statistical parameters is developed, and applied to new lead CDK4 drug discovery.•Scaffold diversity and good predicted activity values are identified for lead drug candidates.•Pharmacokinetic parameters of the new leads are within the acceptable range.