Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors
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| 024 | 7 | 0 | |a 10.1007/s00894-015-2837-4 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00894-015-2837-4 | ||
| 245 | 0 | 0 | |a Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors |h [Elektronische Daten] |c [Naga Tripuraneni, Mohammed Azam] |
| 520 | 3 | |a 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 | |
| 540 | |a Springer-Verlag Berlin Heidelberg, 2015 | ||
| 690 | 7 | |a Docking study |2 nationallicence | |
| 690 | 7 | |a Molecular dynamics |2 nationallicence | |
| 690 | 7 | |a Pharmacophore hypotheses |2 nationallicence | |
| 690 | 7 | |a Phosphodiesterase 4B |2 nationallicence | |
| 690 | 7 | |a Pyrozolopyridine |2 nationallicence | |
| 700 | 1 | |a Tripuraneni |D Naga |u Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India |4 aut | |
| 700 | 1 | |a Azam |D Mohammed |u Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India |4 aut | |
| 773 | 0 | |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/11(2015-11-01), 1-12 |x 1610-2940 |q 21:11<1 |1 2015 |2 21 |o 894 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00894-015-2837-4 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00894-015-2837-4 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Tripuraneni |D Naga |u Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Azam |D Mohammed |u Department of Pharmaceutical Chemistry, J.S.S. College of Pharmacy (Constituent College of JSS University, Mysore), 643001, Udhagamandalam, Tamil Nadu, India |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Modeling |d Springer Berlin Heidelberg |g 21/11(2015-11-01), 1-12 |x 1610-2940 |q 21:11<1 |1 2015 |2 21 |o 894 | ||