Discovery of small-molecule ligands of retinoblastoma-associated protein Rb1 using artificial intelligence

March 09, 2022
Events, ACS2022

At the American Chemical Society Spring National Meeting & Expo, Atomwise members were selected to present their research and work. Learn what our Atoms have been working on below and visit Atomwise at ACS Spring 2022 National Meeting for other presentation sessions. 

tigran-abramyan-256x256Tigran Abramyan, PhD 

Co-Authors: Gary Eitzen; Douglas Zochodne

Title: Discovery of small-molecule ligands of retinoblastoma-associated protein Rb1 using artificial intelligence

Division: Medicinal Chemistry



Retinoblastoma-associated protein Rb1 is widely expressed in adult sensory neurons and their axons during regeneration. Tumor suppressor pathways such as Rb1 may offer novel targets capable of altering the plasticity of post-mitotic adult neurons. Previously Zochodne lab showed that in adult sensory neurons Rb1 short interfering RNA knockdown or Rb1 deletion in vitro enhanced neurite outgrowth and branching, thereby promoting adult neuron regeneration. In this study, using the AtomNet® model, a deep convolutional neural network for structure-based drug discovery, we performed a virtual screen of millions of compounds against Rb1. We discovered several potential small drug-like molecules validated by surface plasmon resonance binding assay and a functional assay measuring the disruption of Rb1-E2F1 association. Encouragingly, some of the discovered compounds of interest promote outgrowth of PC12 cells that can be differentiated into neuronal like cells with nerve growth factors.


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