Structural findings of cinnolines as anti-schizophrenic PDE10A inhibitors through comparative chemometric modeling.
Schizophrenia is a complex psychiatric disorder associated with the distortion of striatopallidal neurotransmission of central nervous system. Phosphodiesterase10A (PDE10A) enzyme plays crucial role in cellular signaling pathways in schizophrenia. Inhibition of this enzyme may facilitate better treatment of this disease. 2D-QSAR, HQSAR, pharmacophore mapping, molecular docking, and 3D-QSAR analyses were performed on 81 cinnoline derivatives having PDE10A inhibitory activity. 2D-QSAR models were developed by multiple linear regression and partial least square analyses using both atom based and whole molecular descriptors. The best model, having considerable internal (q(2) = 0.812) and external (R(2)(pred) = 0.691) predictabilities, demonstrated importance of atom-based topological and whole molecular E-state as well as 3D topological indices. The best HQSAR model was also found to be statistically significant (q(2) = 0.664, R(2)(pred) = 0.513) and it highlighted some important structural features. PHASE-based pharmacophore hypothesis showed the importance of three hydrogen bond acceptor and one each of ring aromatic and hydrophobic features for higher activity. 3D-QSAR CoMFA and CoMSIA models were generated on two different types of alignment procedures-(1) pharmacophore (PHASE) based and (2) docking (GLIDE) based. GLIDE-based alignment produced better results for both CoMFA (Q(2) = 0.578; R(2)(pred) = 0.841) and CoMSIA (Q(2) = 0.610; R(2)(pred) = 0.824) methods. Molecular dynamics (MDs) simulations were performed for two ligand-receptor complexes and these simulations explored some crucial factors for higher activity. These findings of MD simulations were consistent with the interpretations obtained from other methods of analyses. The current study may help in designing new PDE10A inhibitors of this class.
Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata , 700032, India.
Chanchal
C
Mondal
Amit Kumar
AK
Halder
Nilanjan
N
Adhikari
Tarun
T
Jha
D019295:Computational Biology / Q000379:methods*; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology
D006574:Heterocyclic Compounds, 2-Ring; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; C476282:cinnoline