Medinafriis1451

Understanding nonadiabatic dynamics is important for chemical and physical processes involving multiple electronic states. Direct nonadiabatic dynamics simulations are often employed to observe such processes on a femtosecond time scale. One often needs to do the simulation on a longer time scale, but direct simulation based on electronic structure calculations of the surfaces and couplings is expensive due to the large number of electronic structure calculations needed for ensemble averaging or simulation of longer-time processes. An alternative approach is to construct an analytical representation of potential energy surfaces (PESs) and couplings, which allows for faster dynamics calculations. Diabatic representations are preferred for such purposes because of the smoothness of the surfaces and couplings and the scalar nature of the couplings. However, many diabatization procedures are complicated by the need to consider orbitals or vector coupling elements, and these can make the process very labor-intensive. To circumvent these difficulties, we here propose diabatization by a deep neural network (DDNN) based on a new architecture for a deep neural network that requires neither orbital input nor vector input. The DDNN method allows convenient and semiautomatic diabatization, and it is demonstrated here for a model problem and for producing diabatic potential energy matrices for thiophenol.Filoviridae, including Ebola (EBOV) and Marburg (MARV) viruses, are emerging pathogens that pose a serious threat to public health. No agents have been approved to treat filovirus infections, representing a major unmet medical need. The selective estrogen receptor modulator (SERM) toremifene was previously identified from a screen of FDA-approved drugs as a potent EBOV viral entry inhibitor, via binding to EBOV glycoprotein (GP). A focused screen of ER ligands identified ridaifen-B as a potent dual inhibitor of EBOV and MARV. Optimization and reverse-engineering to remove ER activity led to a novel compound 30 (XL-147) showing potent inhibition against infectious EBOV Zaire (0.09 μM) and MARV (0.64 μM). Mutagenesis studies confirmed that inhibition of EBOV viral entry is mediated by the direct interaction with GP. Importantly, compound 30 displayed a broad-spectrum antifilovirus activity against Bundibugyo, Tai Forest, Reston, and Měnglà viruses and is the first submicromolar antiviral agent reported for some of these strains, therefore warranting further development as a pan-filovirus inhibitor.Capuramycin displays a narrow spectrum of antibacterial activity by targeting bacterial translocase I (MraY). In our program of development of new N-acetylglucosaminephosphotransferase1 (DPAGT1) inhibitors, we have identified that a capuramycin phenoxypiperidinylbenzylamide analogue (CPPB) inhibits DPAGT1 enzyme with an IC50 value of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does not show cytotoxicity against normal cells and a series of cancer cell lines. However, CPPB inhibits migrations of several solid cancers including pancreatic cancers that require high DPAGT1 expression in order for tumor progression. DPAGT1 inhibition by CPPB leads to a reduced expression level of Snail but does not reduce E-cadherin expression level at the IC50 (DPAGT1) concentration. CPPB displays a strong synergistic effect with paclitaxel against growth-inhibitory action of a patient-derived pancreatic adenocarcinoma, PD002 paclitaxel (IC50 1.25 μM) inhibits growth of PD002 at 0.0024-0.16 μM in combination with 0.10-2.0 μM CPPB (IC50 35 μM).The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. FR 180204 Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activity and other diverse pharmacological activities. To improve activity and targeting, we designed and prepared 41 semisynthetic analogues of WA. Biological evaluation indicated that the most promising compound 13a displayed the most significant effect on HT-29 cells (human colon cancer cells) (IC50 = 0.08 μM). A structure-activity relationship study indicated that α,β-unsaturated ketones and ester are necessary groups, allowing 13a to undergo Michael addition reactions with mercaptan and selenol. Liquid chromatography-mass spectrometry (LC-MS) analysis confirmed that 13a modified selenocysteine 498 (U) residues in the redox centers of TrxR, resulting in enzyme inhibition. Therefore, compound 13a acts as a novel TrxR inhibitor and may be a promising candidate for cancer intervention.Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn2+ and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and in vitro evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.We present a self-consistent approach for computing the correlated quasiparticle spectrum of charged excitations in iterative O [ N 5 ] computational time. This is based on the auxiliary second-order Green's function approach [Backhouse, O. J. Chem. Theory Comput., 2000], in which a self-consistent effective Hamiltonian is constructed by systematically renormalizing the dynamical effects of the self-energy at second-order perturbation theory. From extensive benchmarking across the W4-11 molecular test set, we show that the iterative renormalization and truncation of the effective dynamical resolution arising from the 2h1p and 1h2p spaces can substantially improve the quality of the resulting ionization potential and electron affinity predictions compared to benchmark values. The resulting method is shown to be superior in accuracy to similarly scaling quantum chemical methods for charged excitations in EOM-CC2 and ADC(2), across this test set, while the self-consistency also removes the dependence on the underlying mean-field reference. The approach also allows for single-shot computation of the entire quasiparticle spectrum, which is applied to the benzoquinone molecule and demonstrates the reduction in the single-particle gap due to the correlated physics, and gives direct access to the localization of the Dyson orbitals.Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor γ (PPARγ). Based on known PPARγ ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed AzoGW1929 and AzoRosi, which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of AzoRosi resulted in the photohormone AzoRosi-4, which bound and activated PPARγ preferentially in its light-activated cis-configuration.Imaging mass spectrometry has become a mature molecular mapping technology that is used for molecular discovery in many medical and biological systems. While powerful by itself, imaging mass spectrometry can be complemented by the addition of other orthogonal, chemically informative imaging technologies to maximize the information gained from a single experiment and enable deeper understanding of biological processes. Within this review, we describe MALDI, SIMS, and DESI imaging mass spectrometric technologies and how these have been integrated with other analytical modalities such as microscopy, transcriptomics, spectroscopy, and electrochemistry in a field termed multimodal imaging. We explore the future of this field and discuss forthcoming developments that will bring new insights to help unravel the molecular complexities of biological systems, from single cells to functional tissue structures and organs.This work presents an in-depth discussion on the nonequilibrium dissociation of O2 molecules colliding with O atoms, combining quasi-classical trajectory calculations, master equation, and dimensionality reduction. A rovibrationally resolved database for all of the elementary collisional processes is constructed by including all nine adiabatic electronic states of O3 in the QCT calculations. A detailed analysis of the ab initio data set reveals that for a rovibrational level, the probability of dissociating is mostly dictated by its deficit in internal energy compared to the centrifugal barrier. Because of the assumption of rotational equilibrium, the conventional vibrational-specific calculations fail to characterize such a dependence. Based on this observation, a new physics-based grouping strategy for application to coarse-grained models is proposed. By relying on a hybrid technique made of rovibrationally resolved excitation coupled to coarse-grained dissociation, the new approach is compared to the vibrational-specific model and the direct solution of the rovibrational state-to-state master equation. Simulations are performed in a zero-dimensional isothermal and isochoric chemical reactor for a wide range of temperatures (1500-20,000 K). The study shows that the main contribution to the model inadequacy of vibrational-specific approaches originates from the incapability of characterizing dissociation, rather than the energy transfers. Even when constructed with only twenty groups, the new reduced-order model outperforms the vibrational-specific one in predicting all of the QoIs related to dissociation kinetics. At the highest temperature, the accuracy in the mole fraction is improved by 2000%.Exploration of [V(bpy)3]2+ and [V(phen)3]2+ (bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline) using electronic spectroscopy reveals an ultrafast excited-state decay process and implicates a pair of low-lying doublets with mixed metal-to-ligand charge-transfer (MLCT) and metal-centered (MC) character. Transient absorption (TA) studies of the vanadium(II) species probing in the visible and near-IR, in combination with spectroelectrochemical techniques and computational chemistry, lead to the conclusion that after excitation into the intense and broad visible 4MLCT ← 4GS (ground-state) absorption band (ε400-700 nm = 900-8000 M-1 cm-1), the 4MLCT state rapidly (τisc less then 200 fs) relaxes to the upper of two doublet states with mixed MLCT/MC character. Electronic interconversion (τ ∼ 2.5-3 ps) to the long-lived excited state follows, which we attribute to formation of the lower mixed state. Following these initial dynamics, GS recovery ensues with τ = 430 ps and 1.6 ns for [V(bpy)3]2+ and [V(phen)3]2+, respectively.