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Abstract Auxetic materials have a negative Poisson’s ratio and are of significant interest in applications that include impact mitigation, membrane separations and biomedical engineering. While there are numerous examples of structured materials that exhibit auxetic behavior, the examples of engineered auxetic structures is largely limited to periodic lattice structures that are limited to directional or anisotropic auxetic response. Structures that exhibit a three-dimensionally isotropic auxetic response have been, unfortunately, slow to evolve. Here we introduce an inverse design algorithm based on global node optimization to design three-dimensional auxetic metamaterial structures from disordered networks. After specifying the target Poisson’s ratio for a structure, an inverse design algorithm is used to adjust the positions of all nodes in a disordered network structure until the desired mechanical response is achieved. The proposed algorithm allows independent control of shear and bulk moduli, while preserving the density and connectivity of the networks. When the angle bending stiffness in the network is kept low, it is possible to realize optimized structures with a Poisson’s ratios as low as −0.6. During the optimization, the bulk modulus of these networks decreases by almost two orders of magnitude, but the shear modulus remains largely unaltered. The materials designed in this manner are fabricated by dual-material 3D-printing, and are found to exhibit the mechanical responses that were originally encoded in the computational design engine. The approach proposed here provides a materials-by-design platform that could be extended for engineering of optical, acoustic, and electrical properties, beyond the design of auxetic metamaterials. 

Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib’s mechanism of Mpro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-Mpro complex. We found that masitinib forms highly stable and specific H-bond interactions with Mpro through its pyridine and aminothiazole rings. Importantly, the interaction with His163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives (M1–M5) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib. 

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus’ main protease, M pro , which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease M pro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.