Identification of nanomolar adenosine A2A receptor ligands using reinforcement learning and structure-based drug design
Morgan Thomas, Pierre Matricon, Robert F. Gillespie, Maja Napiórkowska, Hannah Neale, Jonathan S. Mason, Jason Brown, Kaan Harwood, Charlotte Fieldhouse, Nigel A. Swain, Tian Geng, Noel M. O’Boyle, Francesca Deflorian, Andreas Bender, Chris de Graaf
Abstract
Abstract Generative chemical language models (CLMs) have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based drug design (SBDD) principles with CLMs to go from protein structure to novel small-molecule ligands, without a priori knowledge of ligand chemistry. Using Augmented Hill-Climb, we successfully optimise multiple objectives within a practical timeframe, including protein-ligand complementarity. Resulting de novo molecules contain known or promising adenosine A 2A receptor ligand chemistry that is not available in commercial vendor libraries, accessing commercially novel areas of chemical space. Experimental validation demonstrates a binding hit rate of 88%, with 50% having confirmed functional activity, including three nanomolar ligands and two novel chemotypes. The two strongest binders are co-crystallised with the A 2A receptor, revealing their binding mechanisms that can be used to inform future iterations of structure-based de novo design, closing the AI SBDD loop.