Citation: MIAO Jun-Qiu, HE Su-Hai, DONG Xiu-Shan, LIANG Tai-Gang, LI Qing-Shan. 3D-QSAR Studies on 3-Substituted N-Benzhydryl-nortropane Analogs as Nociception Receptor Agonists[J]. Chinese Journal of Structural Chemistry, ;2016, 35(9): 1319-1327. doi: 10.14102/j.cnki.0254-5861.2011-1104 shu

3D-QSAR Studies on 3-Substituted N-Benzhydryl-nortropane Analogs as Nociception Receptor Agonists

1.
a College of Pharmacy, Shanxi Medical University, Taiyuan 030001, China;
2.
b Department of General Surgery, Shanxi Dayi Hospital, Taiyuan 030032, China

Received Date: 29 December 2015
Available Online: 25 May 2016
Fund Project: This work was supported by the National Natural Science Foundation of China (No. 81101687) (No. 81101687)

The nociceptin receptor(NOP) has been involved in multiple biological functions, including pain, anxiety, cough, substance abuse, cardiovascular control, and immunity. Thus, selective NOP agonists might have clinical potential for the treatment of related diseases. In the present work, three-dimensional quantitative structure-activity relationship(3D-QSAR) studies were performed on a series of 3-substituted N-benzhydryl-nortropane analogs as NOP agonists using comparative molecular field analysis(Co MFA) and comparative molecular similarity indices analysis(CoM SIA) techniques. The statistically significant models were obtained with 54 compounds in training set by ligand-based atom-by-atom matching alignment. The CoM FA model gave cross-validated coefficient(q²) value of 0.530 using 6 components, non-cross-validated(r²) value of 0.921 with estimated F value of 93.668, and standard error of estimate(SEE) of 0.185. The best Co MSIA model resulted in q²=0.592, r²=0.945, N=10, SEE=0.162, and F=75.654, based on steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The predictive ability of the Co MFA and CoM SIA models was further validated using a test set of 18 molecules that were not included in the training set, which resulted in predictive correlation coefficients(r_pred²) of 0.551 and 0.637, respectively. Moreover, the CoM FA and CoM SIA contour maps identified the features important for exhibiting potent binding affinities on NOP, and can thus serve as a useful guide for the design of potential NOP agonists.
- QSAR,
- CoMFA,
- CoMSIA,
- 3-substituted N-benzhydryl-nortropane analogs,
- nociception receptor agonists
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