Two- and Three-Dimensional Quantitative Structure-Activity Relationships Studies on a Series of Liver X Receptor Ligands

Abstract

Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r2 = 0.98 and q2 = 0.69; HQSAR, r2 = 0.99 and q2 = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency.

Adverse Outcome Pathways and Drug-Induced Liver Injury Testing

“…By doing so, a number of chemical features, such as the presence of phenyl rings, chloro groups and methyl moieties, have been identified as determinants of liver X receptor binding and activity. 50 While such approaches typically start from toxicological mechanisms and then search for chemical structures that can trigger them, other strategies may work the other way around. For instance, using a dataset of over nine hundred drugs, sixteen structural alerts for hepatotoxicity in humans have been developed and a mechanistic rationale has been proposed to hypothesize MIEs leading to DILI.…”

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

“…Quantitative structure–activity relationships studies have been successfully applied to optimize different properties for a considerable amount of hit compounds in drug design projects. Two‐dimensional QSAR methods permit not only the investigation of several biological properties for a huge number of compounds but can also be employed in those cases when 3D biological target information is not available (33–37). One of such methods is HQSAR, which requires only 2D structures and the corresponding biological activity as input, allowing the investigation of a wide variety of bioactive compounds (38,39).…”

Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity

“…Two-dimensional and three-dimensional QSAR studies have also been performed on ligands of the liver X receptor, which constitutes the MIE in the AOP on drug-induced steatosis. By doing so, a number of chemical features, such as the presence of phenyl rings, chloro groups and methyl moieties, have been identified as determinants of liver X receptor binding and activation (35).…”