caa a22 4500 605513724 CHVBK 20210128100701.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00894-015-2837-4 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2837-4 Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors [Elektronische Daten] [Naga Tripuraneni, Mohammed Azam] 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 (r2 = 0.8147), regression coefficient (R2 = 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 Springer-Verlag Berlin Heidelberg, 2015 Docking study nationallicence Molecular dynamics nationallicence Pharmacophore hypotheses nationallicence Phosphodiesterase 4B nationallicence Pyrozolopyridine nationallicence Tripuraneni Naga Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India aut Azam Mohammed Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-12 1610-2940 21:11<1 2015 21 894 https://doi.org/10.1007/s00894-015-2837-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2837-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tripuraneni Naga Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India aut NATIONALLICENCE 700 1- Azam Mohammed Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/11(2015-11-01), 1-12 1610-2940 21:11<1 2015 21 894