Quantitative Structure-activity Relationship (QSAR) Modelling of Indomethacin Derivatives using Regression Analysis

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), reduces fever and pain by inhibiting prostaglandin synthesis.
• Understanding the structure-activity relationships of indomethacin derivatives is crucial for developing more potent analogs.

Purpose of the Study:

• To develop a quantitative structure-activity relationship (QSAR) model for indomethacin derivatives.
• To identify key molecular descriptors influencing the anti-inflammatory activity of these compounds.
• To guide the design of novel indomethacin analogs with improved potency.

Main Methods:

• Fifteen indomethacin derivatives were analyzed for their physicochemical and molecular properties.
• 2D and 3D structures were generated, and various topological and quantum chemical descriptors were calculated using software like Chem Sketch, E Dragon, CORINA, and Gauss View.
• Density functional theory (DFT) calculations were performed, including optimization and vibrational frequency analysis.

Main Results:

• A QSAR model (pIC50 = -20.605 IOR - 0.747 I1 - 5.083 Xeq + 51.647) with high statistical significance (R=0.921, R2=0.848) was developed.
• Descriptors such as index of refraction (IOR) and Xeq were found to be significant for activity modeling.
• Combinations of descriptors including Wiener index (W), Balaban centric index (BAC), and molecular connectivity (χ) were important.

Conclusions:

• The QSAR model indicates that lower index of refraction and less electronegative substituents favor activity.
• Specific functional groups, like CH2CH2NHCONH(CH2)3ONO2 at the R1 position, were found to be unfavorable.
• The validated model demonstrates reliability and predictability, offering a valuable tool for designing potent indomethacin analogs.