Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors.
Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited π-π stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4-dimethylpyrazolones.
Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), Udhagamandalam, 643001, Tamil Nadu, India.
Naga Srinivas
NS
Tripuraneni
Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), Udhagamandalam, 643001, Tamil Nadu, India. afzal9azam@hotmail.com.
Mohammed Afzal
MA
Azam
D001665:Binding Sites; D020134:Catalytic Domain; D055808:Drug Discovery; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry*; D047069:Pyrazolones / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
C572644:4,4-dimethylpyrazolone; D058988:Phosphodiesterase 4 Inhibitors; D047069:Pyrazolones; D011725:Pyridines
Docking study; Molecular dynamics; Pharmacophore hypotheses; Phosphodiesterase 4B; Pyrozolopyridine