TY - JOUR
T1 - In-silico designing and characterization of binding modes of two novel inhibitors for CB1 receptor against obesity by classical 3D-QSAR approach
AU - Khan, Naveed
AU - Halim, Sobia Ahsan
AU - Khan, Waqasuddin
AU - Zafar, Syed Kashif
AU - Ul-Haq, Zaheer
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/6
Y1 - 2019/6
N2 - Obesity is the fifth primary hazard for mortality in the world; hence different therapeutic targets are explored to overcome this problem. Endocannabinoid is identified as the emerging target for the treatment of obesity as Cannabinoid 1 (CB1) receptor over-activation resulted in abdominal obesity. Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs. Here, ligand-based 3D-QSAR studies was performed on 100 analogues belonging to a class of 1,2,4-tirazole containing diarylpyrazolylcarboxamide as CB1 receptor antagonists. We developed three CoMFA models using different charge schemes, AM1BCC, Gasteiger-Huckle and MMFF. These models produced almost similar statistical results (q 2 cv = 0.725, 0.692, 0.719 and r 2 ncv = 0.929, 0.924, 0.928 for AM1BCC, Gasteiger-Huckle and MMFF, respectively). The said models were validated through 20 external test set compounds which resulted in significant r 2 pred values (r 2 pred = 0.747, 0.743 and 0.745 for AM1BCC, Gasteiger-Huckle and MMFF, respectively). Comparatively, AM1BCC model provided slightly better statistics among all three tested charges scheme models, hence AM1BCC model was further utilized to generate CoMSIA models considering different field combinations. The best selected CoMSIA model also produced substantial q 2 cv = 0.788, r 2 ncv = 0.916 and r 2 pred = 0.836 values. Furthermore, two new molecules were designed by modifying the same scaffolds on the basis contour map analysis. The activities of newly designed molecules were predicted through obtained CoMFA model ranked as better than their parent molecules. Moreover, these newly designed compounds were successfully docked on the complex crystal structure of CB1 receptor (PDB ID: 5XRA). The docked conformation of these newly designed inhibitor interacted with Ser173, His178, Lys192, Thr197 and Ser383 mainly by hydrophobic and pi-pi stacking interactions. The obtained results signify the potential of the developed model; suggesting that the models can be useful to test and design potent novel CB1 receptor antagonists or inverse agonists prior to the synthesis.
AB - Obesity is the fifth primary hazard for mortality in the world; hence different therapeutic targets are explored to overcome this problem. Endocannabinoid is identified as the emerging target for the treatment of obesity as Cannabinoid 1 (CB1) receptor over-activation resulted in abdominal obesity. Potent antagonists or inverse agonists for CB1 receptor are the new strategies to develop anti-obesity drugs. Here, ligand-based 3D-QSAR studies was performed on 100 analogues belonging to a class of 1,2,4-tirazole containing diarylpyrazolylcarboxamide as CB1 receptor antagonists. We developed three CoMFA models using different charge schemes, AM1BCC, Gasteiger-Huckle and MMFF. These models produced almost similar statistical results (q 2 cv = 0.725, 0.692, 0.719 and r 2 ncv = 0.929, 0.924, 0.928 for AM1BCC, Gasteiger-Huckle and MMFF, respectively). The said models were validated through 20 external test set compounds which resulted in significant r 2 pred values (r 2 pred = 0.747, 0.743 and 0.745 for AM1BCC, Gasteiger-Huckle and MMFF, respectively). Comparatively, AM1BCC model provided slightly better statistics among all three tested charges scheme models, hence AM1BCC model was further utilized to generate CoMSIA models considering different field combinations. The best selected CoMSIA model also produced substantial q 2 cv = 0.788, r 2 ncv = 0.916 and r 2 pred = 0.836 values. Furthermore, two new molecules were designed by modifying the same scaffolds on the basis contour map analysis. The activities of newly designed molecules were predicted through obtained CoMFA model ranked as better than their parent molecules. Moreover, these newly designed compounds were successfully docked on the complex crystal structure of CB1 receptor (PDB ID: 5XRA). The docked conformation of these newly designed inhibitor interacted with Ser173, His178, Lys192, Thr197 and Ser383 mainly by hydrophobic and pi-pi stacking interactions. The obtained results signify the potential of the developed model; suggesting that the models can be useful to test and design potent novel CB1 receptor antagonists or inverse agonists prior to the synthesis.
KW - 3D-QSAR
KW - CB1 receptor
KW - CoMFA and CoMSIA
KW - Endocannabinoid system
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85063254289&partnerID=8YFLogxK
U2 - 10.1016/j.jmgm.2019.03.016
DO - 10.1016/j.jmgm.2019.03.016
M3 - Article
C2 - 30908997
AN - SCOPUS:85063254289
SN - 1093-3263
VL - 89
SP - 199
EP - 214
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
ER -