Molecular recognition of ITIM/ITSM domains with SHP2 and their allosteric effect.

Src homology 2-domain-containing tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase that is widely expressed in a variety of cells and regulates the immune response of T cells through the PD-1 pathway. However, the activation mechanism and allosteric effects of SHP2 remain unclear, hindering the development of small molecule inhibitors. For the first time, in this study, the complex structure formed by the intact PD-1 tail and SHP2 was modeled. The molecular recognition and conformational changes of inactive/active SHP2 versus ITIM/ITSM were compared based on prolonged MD simulations. The relative flexibility of the two SH2 domains during MD simulations contributes to the recruitment of ITIM/ITSM and supports the subsequent conformational change of SHP2. The binding free energy calculation shows that inactive SHP2 has a higher affinity for ITIM/ITSM than active SHP2, mainly because the former's N-SH2 refers to the α-state. In addition, a significant decrease in the contribution to the binding energy of certain residues (e.g., R32, S34, K35, T42, and K55) of conformationally transformed SHP2 contributes to the above result. These detailed changes during conformational transition will provide theoretical guidance for the molecular design of subsequent novel anticancer drugs.

S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism.

CONTEXT: Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. SQ109 is an ethambutol (EMB) analogue, as a novel anti-tuberculosis drug, can effectively inhibit MmpL3, and has completed phase 2b-3 clinical trials. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows significant resistance to the inhibitor SQ109, while the specific action mechanism remains unclear. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport efficiency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant but also aids the development of novel anti-tuberculosis inhibitors. METHODS: In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics, and H-bond energy change of MmpL3 after S288T mutation. In addition, the WT_SQ109 complex structure was obtained by molecular docking program (Autodock 4.2); Molecular Mechanics/ Poisson Boltzmann Surface Area (MM-PBSA) and Solvated Interaction Energy (SIE) methods were used to calculate the binding free energies (∆Gbind); Geometric criteria were used to analyze the changes of hydrogen bond networks.

Pt(IV) Prodrug Photoactivation: A Promising Strategy for Cancer Therapy.

Platinum (II) drugs, including cisplatin, carboplatin, and oxaliplatin, have achieved significant clinical success in cancer treatment. However, their clinical application has been greatly hindered by various adverse factors such as non-specific activation and drug resistance. Compared with Pt(II) drugs, the axial ligands within Pt(IV) compounds can improve the pharmacokinetic properties, selectivity, and biological activity, implementing alternative cytotoxic mechanisms beyond DNA cross-linking and partially overcoming drug resistance. The controlled conversion of Pt(IV) prodrugs into Pt(II) agents at the tumor site has been extensively explored internationally. In this review, Pt(IV) prodrug modification strategies are first summarized, next the development of the predominant external and internal photosensitizers is listed. Finally, three representative photoreduction mechanisms and strategies for developing corresponding Pt(IV) prodrugs are discussed. This work provides constructive instruction for the subsequent molecular design of Pt(IV) prodrugs.

Altered resting-state functional connectivity in newborns with hypoxic ischemic encephalopathy assessed using high-density functional near-infrared spectroscopy.

Hypoxic-ischemic encephalopathy (HIE) results from a lack of oxygen to the brain during the perinatal period. HIE can lead to mortality and various acute and long-term morbidities. Improved bedside monitoring methods are needed to identify biomarkers of brain health. Functional near-infrared spectroscopy (fNIRS) can assess resting-state functional connectivity (RSFC) at the bedside. We acquired resting-state fNIRS data from 21 neonates with HIE (postmenstrual age [PMA] = 39.96), in 19 neonates the scans were acquired post-therapeutic hypothermia (TH), and from 20 term-born healthy newborns (PMA = 39.93). Twelve HIE neonates also underwent resting-state functional magnetic resonance imaging (fMRI) post-TH. RSFC was calculated as correlation coefficients amongst the time courses for fNIRS and fMRI data, respectively. The fNIRS and fMRI RSFC maps were comparable. RSFC patterns were then measured with graph theory metrics and compared between HIE infants and healthy controls. HIE newborns showed significantly increased clustering coefficients, network efficiency and modularity compared to controls. Using a support vector machine algorithm, RSFC features demonstrated good performance in classifying the HIE and healthy newborns in separate groups. Our results indicate the utility of fNIRS-connectivity patterns as potential biomarkers for HIE and fNIRS as a new bedside tool for newborns with HIE.