Pretrained Joint Predictions for Scalable Batch Bayesian Optimization of Molecular Designs

Batched synthesis and testing of molecular designs is the key bottleneck of drug development. There has been great interest in leveraging biomolecular foundation models as surrogates to accelerate this process. In this work, we show how to obtain scalable probabilistic surrogates of binding affinity for use in Batch Bayesian Optimization (Batch BO). This demands parallel acquisition functions that hedge between designs and the ability to rapidly sample from a joint predictive density to approximate them. Through the framework of Epistemic Neural Networks (ENNs), we obtain scalable joint predictive distributions of binding affinity on top of representations taken from large structure-informed models. Key to this work is an investigation into the importance of prior networks in ENNs and how to pretrain them on synthetic data to improve downstream performance in Batch BO. Their utility is demonstrated by rediscovering known potent EGFR inhibitors on a semi-synthetic benchmark in up to 5x fewer iterations, as well as potent inhibitors from a real-world small-molecule library in up to 10x fewer iterations, offering a promising solution for large-scale drug discovery applications.

Sample-and-Accumulate Algorithms for Belief Updating in Bayes Networks

Belief updating in Bayes nets, a well known computationally hard problem, has recently been approximated by several deterministic algorithms, and by various randomized approximation algorithms. Deterministic algorithms usually provide probability bounds, but have an exponential runtime. Some randomized schemes have a polynomial runtime, but provide only probability estimates. We present randomized algorithms that enumerate high-probability partial instantiations, resulting in probability bounds. Some of these algorithms are also sampling algorithms. Specifically, we introduce and evaluate a variant of backward sampling, both as a sampling algorithm and as a randomized enumeration algorithm. We also relax the implicit assumption used by both sampling and accumulation algorithms, that query nodes must be instantiated in all the samples.