17th Winter Conference on Medicinal & Bioorganic Chemistry
- February 2nd-6th, 2025
- Steamboat Springs, Colorado
Schrödinger is excited to be participating in the 17th Winter Conference on Medicinal & Bioorganic Chemistry taking place on February 2nd – 6th in Steamboat Springs, Colorado. Join us for a poster presentation by Gang Wang, Principal Scientist II at Schrödinger, titled “Pairing machine learning and FEP+ enables the discovery of P38-MK2 molecular glues.”
Pairing machine learning and FEP+ enables the discovery of P38-MK2 molecular glues
Speaker:
Gang Wang, Principal Scientist II, Schrödinger
Abstract:
Mitogen activating protein kinases (MAPK)-activated kinase MK2 phosphorylates AU-rich element binding proteins (AUBPs) that modulate the stability of cytokine mRNA. An emerging class of inhibitors create a ternary complex with upstream kinase p38 and MK2. These molecular glues demonstrate superior properties relative to orthosteric inhibitors of either p38 or MK2 but their mechanism of action presents challenges to computationally driven design. Herein we describe our computational design strategy, including the use of FEP+ coupled with Machine Learning (e.g., AutoDesigner and AL-FEP+), to discover multiple structurally diverse, potent, and highly selective molecular glues. Compounds 1 and 2 demonstrate pronounced reduction in TNFα levels after PO dosing in LPS mouse models and represent the validation of our modeling workflow for challenging molecular glues.