While virtual reality (VR) is emerging as an interactive tool for chemical education, its application and assessment for chemical education are still limited. Thus, an educational VR activity based on interactive molecular dynamics in virtual reality (iMD-VR), which allows for realtime, immersive interactions with a dynamic molecular world, was now designed and executed to demonstrate chemical concepts and engage students in exploring molecular structures, motions, and interactions. There were 70 students in the first semester of an introductory organic chemistry course asked to complete an example task to pull a methane molecule through a carbon nanotube with iMD-VR software originally designed for research purposes by Glowacki and coworkers. Our assessments of this activity have shown valuable motivational impacts and measurable learning gains. The VR activity can be further tailored to many different levels by varying the topics and tasks, with affordable hardware and software.

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.

Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC = 13 nM) without significant inhibition of HepG2 cells (IC > 50 μM). 18a was also tested in a luciferase-based Plasmodium berghei mouse model of malaria and showed exceptional in vivo efficacy. Together, the data support MEPicide 18a as a novel, potent, and promising drug candidate for the treatment of malaria.

We report an original catalytic molecular tetrahedron. By threading through the cavity of the tetrahedron, polymeric substrates are unfolded or broken apart. Our catalyst distinguishes between polymer chains of different lengths, functionalizing the shorter polymers selectively over the longer ones-as a proof of concept for selective catalysis to modify polymers. Our findings advance the fundamental understanding of the thermodynamic and kinetic phenomena controlling the interactions between molecular cages and synthetic polymers, offering valuable ability to create complex materials in the future.

Large-scale conformational transitions in the spike protein S2 domain are required during host cell infection of the SARS-CoV-2 virus. Although conventional molecular dynamics simulations have been extensively used to study therapeutic targets of SARS-CoV-2, it is still challenging to gain molecular insight into the key conformational changes due to the size of the spike protein and the long timescale required to capture these transitions. In this work, we have developed an efficient simulation protocol that leverages many short simulations, a novel selection algorithm, and Markov state models to interrogate the dynamics of the S2 domain. We discovered that the conformational flexibility of the dynamic region upstream of the fusion peptide in S2 is coupled to the proteolytic cleavage state of the spike protein. These results suggest that opening of the fusion peptide likely occurs on a sub-microsecond timescale following cleavage at the S2’ site. Building on the structural and dynamical information gained to date about S2 domain dynamics, we provide proof-of-principle that a small molecule bound to a seam neighboring the fusion peptide can slow the opening of the fusion peptide, leading to a new inhibition strategy for experiments to confirm. In aggregate, these results will aid the development of drug cocktails to inhibit infections caused by SARS-CoV-2 and other coronaviruses.