Structure-activity relationship: analyses of p-glycoprotein substrates and inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• P-glycoprotein (p-gp) is a key transporter involved in multidrug resistance (MDR).
• Numerous compounds interact with p-gp as substrates or modulators, but few clinically promising MDR-reversing agents have been developed.
• Understanding structure-activity relationships (SAR) is crucial for designing effective p-gp modulators.

Purpose of the Study:

• To uncover factors significantly impacting the interaction between p-gp substrates/modulators and p-gp.
• To perform SAR analyses on p-gp substrates/modulators and clinically promising MDR-reversing agents.
• To identify key physicochemical and structural properties for effective p-gp modulation.

Main Methods:

• Structure-activity relationship (SAR) analyses were conducted.
• Molecular modeling, 2D and 3D parameter-frame-setting, and quantitative structure-activity relationship (QSAR) analyses were employed.
• Physicochemical parameters (C log P, CMR, log Mw, Nlc, Ehomo) were calculated using specialized software (C log P, CQSAR, HyperChem).

Main Results:

• MDR reversal activity correlated with lipophilicity (C log P), molecular weight (log Mw), molecular axis length (Nlc), and highest occupied orbital energy (Ehomo).
• The presence of a basic tertiary nitrogen atom is crucial for p-gp inhibitory activity.
• 3D-parameter-frame setting using Nlc, C log P, and Ehomo effectively separated p-gp substrates and inhibitors.

Conclusions:

• Effective p-gp modulators require a log P value ≥ 2.92, a molecular axis length ≥ 18 atoms, high Ehomo, and at least one tertiary basic nitrogen atom.
• These findings enhance understanding of drug-p-gp interactions.
• The results provide a basis for developing novel MDR chemosensitizers.