Multiple Computational Approaches for Predicting Drug Interactions with Human Equilibrative Nucleoside Transporter 1

Area of Science:

• Pharmacology
• Computational Chemistry
• Drug Discovery

Background:

• Equilibrative nucleoside transporters (ENTs) are crucial for nucleoside analog drug pharmacokinetics.
• Understanding ENT interactions facilitates the development of chemotherapeutics and antivirals, especially for sanctuary sites like the male genital tract.

Purpose of the Study:

• To create three-dimensional pharmacophores for ENT1 and ENT2 substrates and inhibitors.
• To computationally predict and experimentally validate drug interactions with human ENTs.

Main Methods:

• Curated K_t and IC₅₀ data from literature to build 3D pharmacophores for ENT1 and ENT2.
• In vitro validation using NBMPR to assess the impact on mizoribine and ribavirin accumulation in ENT1 and ENT2 cells.
• Evaluated darunavir's interaction with ENTs, assessing NBMPR's influence on its cellular accumulation.

Main Results:

• Distinct substrate pharmacophores for ENT1 and ENT2 were identified, with partial overlap in hydrogen bond donors.
• Inhibitor pharmacophores predominantly featured hydrogen bond acceptors.
• Mizoribine and ribavirin were confirmed as ENT substrates, with NBMPR significantly decreasing their cellular accumulation.
• Darunavir acted as an ENT inhibitor, with NBMPR not significantly affecting its accumulation, confirming limited interaction.

Conclusions:

• Developed and validated computational models for human ENTs (ENT1 and ENT2) to predict drug interactions.
• These models can guide compound selection in drug discovery, reducing development time and costs.
• Predicting ENT substrates aids in identifying drugs capable of penetrating tissues expressing these transporters.