Can Deep Learning Blind Docking Methods be Used to Predict Allosteric Compounds?

Allosteric compounds offer an alternative mode of inhibition to orthosteric compounds with opportunities for selectivity and noncompetition. Structure-based drug design (SBDD) of allosteric compounds introduces complications compared to their orthosteric counterparts; multiple binding sites of interest are considered, and often allosteric binding is only observed in particular protein conformations. Blind docking methods show potential in virtual screening allosteric ligands, and deep learning methods, such as DiffDock, achieve state-of-the-art performance on protein–ligand complex prediction benchmarks compared to traditional docking methods such as Vina and Lin_F9. To this aim, we explore the utility of a data-driven platform called the minimum distance matrix representation (MDMR) to retrospectively predict recently discovered allosteric inhibitors complexed with Cyclin-Dependent Kinase (CDK) 2. In contrast to other protein complex representations, it uses the minimum residue–residue (or residue–ligand) distance as a feature that prioritizes the formation of interactions. Analysis of this representation highlights the variety of protein conformations and ligand binding modes, and we identify an intermediate protein conformation that other heuristic-based kinase conformation classification methods do not distinguish. Next, we design self- and cross-docking benchmarks to assess whether docking methods can predict both orthosteric and allosteric binding modes and if prospective success is conditional on the selection of the protein receptor conformation, respectively. We find that a combined method, DiffDock followed by Lin_F9 Local Re-Docking (DiffDock + LRD), can predict both orthosteric and allosteric binding modes, and the intermediate conformation must be selected to predict the allosteric pose. In summary, this work highlights the value of a data-driven method to explore protein conformations and ligand binding modes and outlines the challenges of SBDD of allosteric compounds.