Research Article: Insights into the Molecular Requirements for the Anti‐obesity Activity of a Series of CB1 Ligands

Abstract

Two-dimensional and 3D quantitative structureactivity relationships studies were performed on a series of diarylpyridines that acts as cannabinoid receptor ligands by means of hologram quantitative structure-activity relationships and comparative molecular field analysis methods. The quantitative structure-activity relationships models were built using a data set of 52 CB1 ligands that can be used as anti-obesity agents. Significant correlation coefficients (hologram quantitative structure-activity relationships: r 2 = 0.91, q 2 = 0.78; comparative molecular field analysis: r 2 = 0.98, q 2 = 0.77) were obtained, indicating the potential of these 2D and 3D models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted (calculated) values are in good agreement with the experimental results. The final quantitative structure-activity relationships models, along with the information obtained from 2D contribution maps and 3D contour maps, obtained in this study are useful tools for the design of novel CB1 ligands with improved anti-obesity potency.

Identifying the structural features and diversifying the chemical domain of peripherally acting CB1 receptor antagonists using molecular modeling techniques

“…The present work was aimed to identify essential structural features for peripherally acting CB1 receptor antagonists. Active (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) indicated that the predicted activities are very close to the actual activities (Table 6). On the basis of threshold value (active > 7.5, inactive < 7.5), sensitivity of the best model was observed as 88.89% indicating that 88.89% of compounds were correctly predicted "actives" out of the total "actives" whereas specicity was observed as 100% which indicated that 100% of compounds were correctly predicted "non-actives" out of the total "inactives".…”

“…The dataset so obtained was divided into a model-building set containing 25 compounds (1-25) as shown in Fig. 1 and an external test set of 10 compounds (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) which were used for the validation of the developed model as shown in Fig. 2.…”

“…All these studies have been directed for centrally acting CB1 receptor antagonists. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Due to the adverse effects reported with centrally acting compounds, designing of selective peripherally acting CB1 receptor antagonists is considered as a novel task. Thus, some molecular modeling techniques were applied for designing of peripherally acting CB1 receptor antagonists.…”

Molecular Features Related to HIV Integrase Inhibition Obtained from Structure- and Ligand-Based Approaches

“…A crucial step in the generation of the CoMFA model is the 3D molecular alignment of the data set [30] , [31] . As mentioned before, the 3D alignment used in this study was based on the molecular docking of the inhibitors in the enzyme active site.…”

Ligand‐ and Structure‐Based Drug Design Strategies and PPARδ/α Selectivity

“…Therefore, new PPARδ‐selective agonists should be developed to help treat several diseases, such as diabetes, metabolic syndrome and atherosclerosis (22). Ligand‐ and structure‐based strategies have been previously employed to develop new bioactive ligands (34–39). In this study, we have used ligand‐ and structure‐based methodologies to identify the most important electronic, hydrophobic and structural features in determining the PPARδ/α selectivity of a series of bioactive ligands.…”