Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1

Area of Science:

• Pharmacology
• Drug Discovery
• Computational Chemistry

Background:

• The liver-specific organic cation transport protein 1 (OCT1; SLC22A1) is crucial for transporting various cationic drugs, including metformin, oxaliplatin, and imatinib.
• Understanding OCT1 inhibition is vital for optimizing drug efficacy and minimizing adverse effects.

Purpose of the Study:

• To investigate the inhibition patterns of OCT1 using a diverse set of registered oral drugs.
• To develop predictive computational models for identifying OCT1 inhibitors.

Main Methods:

• A total of 191 structurally diverse compounds were screened for OCT1 inhibition in HEK293-OCT1 cells.
• Physicochemical properties of inhibitors and non-inhibitors were analyzed.
• Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) models were generated.

Main Results:

• The study identified 47 novel OCT1 inhibitors and confirmed 15 known inhibitors.
• Drug classes such as antidepressants showed enrichment of OCT1 inhibitors.
• High lipophilicity and positive net charge were identified as key physicochemical drivers of OCT1 inhibition.
• High molecular dipole moment and numerous hydrogen bonds were negatively correlated with OCT1 inhibition.
• The final OPLS-DA model achieved 82% accuracy in predicting inhibitors and 88% in predicting non-inhibitors.

Conclusions:

• Physicochemical properties like lipophilicity and charge are critical determinants of OCT1 inhibition.
• Predictive computational models can effectively identify potential OCT1 inhibitors among existing drug compounds.
• These findings aid in the rational design and selection of drugs targeting OCT1-mediated transport.