PandaDock: An Open-Source Molecular Docking Platform with Flexible-Ligand Search and Equivariant Neural Scoring

Abstract

We present PandaDock, an open-source molecular docking platform implementing flexible-ligand conformational search with analytic gradients, a precomputed affinity grid engine, specialized modules for induced-fit, metal-coordination and tethered docking, and an SE(3)-equivariant graph neural network scoring function trained at scale. Ligand flexibility is represented as a torsion tree and pose parameters are optimized by Monte Carlo with Metropolis acceptance refined by L-BFGS, with rotational gradients obtained in closed form through the derivative of the SO(3) exponential map rather than by finite differences. Affinity grids are built by a blocked neighbor-selection scheme that is exact and 5.6-9.7x faster than dense evaluation, and may be cached across ligands sharing a receptor and site, reducing a six-ligand series from 29.3 s to 10.4 s. On 814 protein-ligand complexes spanning 14 target families, PandaDock recovers a pose within 2 Angstroms of the crystal geometry in 33.7% of cases at rank 1 and in 57.0% of cases within the returned ensemble. The GNN scoring function is trained on 741,706 co-folded complexes from SAIR under target-disjoint splits, reaching a Pearson r of 0.407 on 90,219 held-out complexes and transferring to 202 independent crystal structures with measured Ki, Kd, IC50 or EC50 at r = 0.467. We report the model against three controls, a target-mean predictor, a ligand-descriptor-only baseline, and within-target correlations, and document both where it performs and where it does not, including its unsuitability for pose rescoring. On an independent 30-compound series against a single GABAA receptor target, PandaDock's empirical scoring function ranks 8th of 25 methods evaluated, ahead of every AutoDock Vina and Vinardo configuration tested, while the GNN scores below Vina, consistent with the within-target ceiling identified on SAIR. At full scale on the PDBbind v2020 refined set (n = 4,640, native crystal poses), the fully independent SAIR model reaches r = 0.531, and a dedicated model trained on PDBbind alone under a target-disjoint split reaches r = 0.690 on its own held-out test complexes, the strongest evidence in this work that PandaDock's affinity predictions generalize. PandaDock is distributed under an open-source license at https://github.com/pritampanda15/PandaDock with a complete command-line interface and a reproducible benchmarking harness.