Transferable Machine Learning Interatomic Potential for Bond Dissociation Energy Prediction of Drug-like Molecules.

We present a transferable MACE interatomic potential that is applicable to open- and closed-shell drug-like molecules containing hydrogen, carbon, and oxygen atoms. Including an accurate description of radical species extends the scope of possible applications to bond dissociation energy (BDE) prediction, for example, in the context of cytochrome P450 (CYP) metabolism. The transferability of the MACE potential was validated on the COMP6 data set, containing only closed-shell molecules, where it reaches better accuracy than the readily available general ANI-2x potential. MACE achieves similar accuracy on two CYP metabolism-specific data sets, which include open- and closed-shell structures. This model enables us to calculate the aliphatic C-H BDE, which allows us to compare reaction energies of hydrogen abstraction, which is the rate-limiting step of the aliphatic hydroxylation reaction catalyzed by CYPs. On the "CYP 3A4" data set, MACE achieves a BDE RMSE of 1.37 kcal/mol and better prediction of BDE ranks than alternatives: the semiempirical AM1 and GFN2-xTB methods and the ALFABET model that directly predicts bond dissociation enthalpies. Finally, we highlight the smoothness of the MACE potential over paths of sp3C-H bond elongation and show that a minimal extension is enough for the MACE model to start finding reasonable minimum energy paths of methoxy radical-mediated hydrogen abstraction. Altogether, this work lays the ground for further extensions of scope in terms of chemical elements, (CYP-mediated) reaction classes and modeling the full reaction paths, not only BDEs.

wfl Python toolkit for creating machine learning interatomic potentials and related atomistic simulation workflows.

Predictive atomistic simulations are increasingly employed for data intensive high throughput studies that take advantage of constantly growing computational resources. To handle the sheer number of individual calculations that are needed in such studies, workflow management packages for atomistic simulations have been developed for a rapidly growing user base. These packages are predominantly designed to handle computationally heavy ab initio calculations, usually with a focus on data provenance and reproducibility. However, in related simulation communities, e.g., the developers of machine learning interatomic potentials (MLIPs), the computational requirements are somewhat different: the types, sizes, and numbers of computational tasks are more diverse and, therefore, require additional ways of parallelization and local or remote execution for optimal efficiency. In this work, we present the atomistic simulation and MLIP fitting workflow management package wfl and Python remote execution package ExPyRe to meet these requirements. With wfl and ExPyRe, versatile atomic simulation environment based workflows that perform diverse procedures can be written. This capability is based on a low-level developer-oriented framework, which can be utilized to construct high level functionality for user-friendly programs. Such high level capabilities to automate machine learning interatomic potential fitting procedures are already incorporated in wfl, which we use to showcase its capabilities in this work. We believe that wfl fills an important niche in several growing simulation communities and will aid the development of efficient custom computational tasks.

ACEpotentials.jl: A Julia implementation of the atomic cluster expansion.

We introduce ACEpotentials.jl, a Julia-language software package that constructs interatomic potentials from quantum mechanical reference data using the Atomic Cluster Expansion [R. Drautz, Phys. Rev. B 99, 014104 (2019)]. As the latter provides a complete description of atomic environments, including invariance to overall translation and rotation as well as permutation of like atoms, the resulting potentials are systematically improvable and data efficient. Furthermore, the descriptor's expressiveness enables use of a linear model, facilitating rapid evaluation and straightforward application of Bayesian techniques for active learning. We summarize the capabilities of ACEpotentials.jl and demonstrate its strengths (simplicity, interpretability, robustness, performance) on a selection of prototypical atomistic modelling workflows.

Neural network activation similarity: a new measure to assist decision making in chemical toxicology.

Deep learning neural networks, constructed for the prediction of chemical binding at 79 pharmacologically important human biological targets, show extremely high performance on test data (accuracy 92.2 ± 4.2%, MCC 0.814 ± 0.093 and ROC-AUC 0.96 ± 0.04). A new molecular similarity measure, Neural Network Activation Similarity, has been developed, based on signal propagation through the network. This is complementary to standard Tanimoto similarity, and the combined use increases confidence in the computer's prediction of activity for new chemicals by providing a greater understanding of the underlying justification. The in silico prediction of these human molecular initiating events is central to the future of chemical safety risk assessment and improves the efficiency of safety decision making.

Scaffold hopping from synthetic RXR modulators by virtual screening and de novo design.

The lack of potent subtype-selective modulators of retinoid X receptors (RXRs) has hindered their full exploitation as promising drug targets. Using computational similarity searching, target prediction and automated de novo design, we identified novel RXR ligands exhibiting innovative molecular frameworks, pronounced receptor-subtype preference and suitable properties for hit-to-lead expansion.

Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics.

Natural products (NPs) are progressively recognized as invaluable source of pharmacological tools and lead structures. To enable NP-inspired retinoid X receptor (RXR) modulator design, three novel RXR-targeting NPs were computationally identified. Among them, valerenic acid was found to be selective for RXRß, rendering it a unique pharmacological tool compound. The NPs then served as templates for automated, ligand-based de novo design of innovative, easily accessible mimetics that inherited the biological activities of their natural templates.