Assessment of Pharmaceutical Protein–Ligand Pose and Affinity Predictions in <scp>CASP16</scp>

The protein-ligand component of the 16th Critical Assessment of Structure Prediction (CASP16) challenged participants to predict both binding poses and affinities of small molecules to protein targets, with a focus on drug-like compounds from pharmaceutical discovery projects. Thirty research groups submitted predictions for 229 protein-ligand pose targets and 140 affinity targets across five protein systems. Among the submitted predictions, template-based pose-prediction methods did particularly well, with the best groups achieving mean LDDT-PLI values of 0.69 (scale of 0-1 with 1 best). For comparison, we also ran a set of automated baseline pose-prediction methods, including ones using deep neural networks. Of these, AlphaFold 3 did particularly well, with a mean LDDT-PLI of 0.8, thus outscoring the best CASP16 predictor. The CASP affinity predictions showed modest correlation with experimental data (maximum Kendall's τ = 0.42), well below the theoretical maximum possible given experimental uncertainty (~0.73). As seen in prior challenges, providing experimental structures did not improve affinity predictions in the second stage of the challenge, suggesting that the scoring functions used here are a key limiting factor. Overall, the accuracy achieved by CASP participants is similar to that observed in the prior Drug Design Data Resource (D3R) blinded prediction challenges. The present results highlight the progress and persistent challenges in computational protein-ligand modeling and provide valuable benchmarks for the field of computer-aided drug design.