Connecting AI
with Chemical Sciences

Machine learned interatomic potentials (MLIPs) are reshaping computational chemistry practices because of their ability to drastically exceed the accuracy-length/time scale tradeoff.

Proteochemometric models (PCMs) are used in computational drug discovery to employ both protein and ligand representations jointly for bioactivity prediction. While machine learning (ML) and deep learning (DL) have come to dominate PCMs, often serving as a basis for scoring functions, rigorous evaluation standards have not always been consistently applied. In this study, using kinase-ligand bioactivity prediction as a model system, we highlight the critical roles of data set curation, permutation testing, class imbalances, and various data splitting strategies for mitigating plausible data leakage and embedding quality in determining model performance. Our findings indicate that data splitting and class imbalances are the most critical factors affecting PCM performance, emphasizing the challenges in the generalizing ability of ML/DL-PCMs. We evaluated various protein–ligand descriptors and embeddings, including those augmented with multiple sequence alignment information. However, permutation testing consistently demonstrated that protein embeddings contributed minimally to PCM efficacy. This study advocates for the adoption of stringent evaluation standards to enhance the generalizability of models to out-of-distribution data and improve benchmarking practices.

Reaction mechanism search tools have demonstrated the ability to provide insights into likely products and rate-limiting steps of reacting systems. However, reactions involving several concerted bond changes─as can be found in many key steps of natural product syntheses─can complicate the search process. To mitigate these complications, we present a mechanism search strategy particularly suited to help expedite exploration of an exemplary family of such complex reactions, cyclizations. We provide a cost-effective strategy for identifying relevant elementary reaction steps by combining graph-based enumeration schemes and machine learning techniques for intermediate filtering. Key to this approach is our use of a neural network potential (NNP), AIMNet2-rxn, for computational evaluation of each candidate reaction pathway. In this article, we evaluate the NNP's ability to estimate activation energies, demonstrate the correct anticipation of stereoselectivity, and recapitulate complex enabling steps in natural product synthesis.