Computational study on the binding mechanism of allosteric drug TNO155 inhibiting SHP2E76A.

E76A mutations of SHP2 have been reported to associate with genetic developmental diseases and cancers, and TNO155 is one of the effective inhibitors targeted to the allosteric site 1, which has already entered the clinical stage. However, the detailed binding mechanism between them still needs further clarification at micro-atomic level. In this study, the binding mechanism of TNO155 inhibiting SHP2E76A and the superiorities of TNO155 at binding affinity and dynamic interactive behavior with SHP2E76A were probed utilizing a series of computational drug design technologies. The results show that SHP2E76A forms tighter interaction with TNO155 compared to SHP099. SHP2E76A-TNO155 exhibits the largest electrostatic interaction among all complex systems, which can be manifested by the strong hydrogen bond interactions formed by two electrically charged residues, Arg111 and Glu250. Notably, in SHP2E76A-TNO155 system, Asp489 makes an additional substantial beneficial contribution. The E76A mutation brings stronger residue positive correlation and a larger conformation fluctuation between N-CH2 and PTP domains, resulting in tighter binding between TNO155 and SHP2E76A. This study offers valuable insights for the further design and development of novel SHP2E76A allosteric inhibitors.

A-site cation manipulation of exemplary second harmonic generation response and optical anisotropy in rare-earth borates.

Ultraviolet nonlinear optical (UV NLO) materials have garnered significant interest for their prospective applications in advanced laser technologies. However, tailoring the desired structure in these materials remains a formidable challenge. Here, we propose a simple yet effective strategy for synthesizing rare-earth borates, K x Na3-x La2B3O9 (x = 2-3), by manipulating the A-site cations to induce structural evolution. Notably, K x Na3-x La2B3O9 undergoes a phase transition from the Pnc2 to the Amm2 space group by adjusting the K+ content to reach x = 2.6. Moreover, the target compounds exhibit strong phase-matching second harmonic generation (SHG) efficiencies, ranging from 1.3 to 3.3 times that of KDP (KH2PO4), and feature short UV cutoff edges of around 204-208 nm. Additionally, the correlation between microscopic polarizability, optical anisotropy, and the structural evolution of these materials was characterized through structural and theoretical analyses. These findings highlight the potential applications of K x Na3-x La2B3O9 as UV NLO materials and underscore the viability of manipulating A-site cations to fabricate NLO crystals with desirable properties.