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At least 631 records · Page 35

Structurally Constrained Evolutionary Algorithm for the Discovery and Design of Metastable Phases

Metastable materials are abundant in nature and technology, showcasing remarkable properties that inspire innovative materials design. However, traditional crystal structure prediction methods, which rely solely on energetic factors to determine a structure’s fitness, are not suitable for predicting the vast number of potentially synthesizable phases that represent a local minimum corresponding to a state in thermodynamic equilibrium. Here, we present a new approach for the prediction of metastable phases with specific structural features, and interface this method with the XTALOPT evolutionary algorithm. Our method relies on structural features that include the local crystalline order (e.g., the coordination number or chemical environment), and symmetry (e.g., Bravais lattice and space group) to filter the breeding pool of an evolutionary crystal structure search. The effectiveness of this approach is benchmarked on three known metastable systems: XeN 8 , with a two-dimensional polymeric nitrogen sublattice, brookite TiO 2 , and a high pressure BaH 4 phase that was recently characterized. Additionally, a newly predicted metastable melaminate salt, P1¯WC 3 N 6 , was found to possess an energy that is lower than two phases proposed in a recent computational study. Here, the method presented here could help in identifying the structures of compounds that have already been synthesized, and developing new synthesis targets with desired properties.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO–TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

60 APPLIED LIFE SCIENCES↗