Virtual Specific Inhibition of Mitochondrial Glycerol 3-Phosphate

Overview

Mitochondrial glycerol 3 -phosphate dehydrogenase (mGPD) is on the outside of the inner mitochondrial membrane and catalyzes the reaction turning glycerol 3-phosphate (G3P) into dihydroxyacetone phosphate (DHAP), which reduces NADH into NAD+, 2 electrons, and a hydrogen proton. mGPD adds electrons and protons into the matrix, causing a proton motive force collapse in the electron transport chain. This leads to the formation of reactive oxygen species (ROS), which damages metabolic processes. Therefore, inhibiting mGPD prevents the formation of ROS. My project investigated the most probable pharmacophore of a compatible inhibitor for mGPD. By using a machine learning model, trained with enzyme recognition and ~1400 substrates, the compatibility of various subs trates with mGPD was calculated. I hypothesized that an inhibitor with multiple guanidine groups may be effective for binding to mGPD because metformin is a biguanide. Additionally, I hypothesized that increasing structural similarity to G3P, the original substrate, would lead to increasing binding compatibility. I ran a collection of substrates, varying numbers of guanidine groups, and structural similarity to G3P, through the machine learning model. The program outputs a score of 0-1, where a score closer to 1 suggests higher compatibility. The data shows no strong association between an increasing number of guanidine groups or structural similarity to G3P and binding compatibility with mGPD. However, results suggest that the phosphate group may be an impo rtant feature of the final inhibitor to demonstrate.

Competition history

• JSHS 2024 Category not listed

Resources

• National JSHS abstract book ↗

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