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Computational theory-driven reports involving encouragement understanding along with decision-making throughout dependency: Precisely what have we realized?
Resonance parameters predicted by the CAP/XMS-CASPT2 method agree well with CAP/SAC-CI results (deviations of about 0.15 eV); however, as expected, CAP/XMS-CASPT2 has clear advantages in the bond dissociation region. The advantages of CAP/XMS-CASPT2 are further demonstrated in the calculations of 4Πu and 2Πu resonance states of N2- including their 3Σu+ and 3Δu parent states. Three of the involved states (2Πu, 3Σu+, and 3Δu) possess multireference character, and CAP/XMS-CASPT2 can easily describe these states with a relatively modest active space.Accurate protein druggability predictions are important for the selection of drug targets in the early stages of drug discovery. Because of the flexible nature of proteins, the druggability of a binding pocket may vary due to conformational changes. We have therefore developed two statistical models, a logistic regression model (TRAPP-LR) and a convolutional neural network model (TRAPP-CNN), for predicting druggability and how it varies with changes in the spatial and physicochemical properties of a binding pocket. These models are integrated into TRAnsient Pockets in Proteins (TRAPP), a tool for the analysis of binding pocket variations along a protein motion trajectory. The models, which were trained on publicly available and self-augmented datasets, show equivalent or superior performance to existing methods on test sets of protein crystal structures and have sufficient sensitivity to identify potentially druggable protein conformations in trajectories from molecular dynamics simulations. Visualization of the evidence for the decisions of the models in TRAPP facilitates identification of the factors affecting the druggability of protein binding pockets.Over the past 70 years, the search for small molecules from nature has transformed biomedical research natural products are the basis for half of all pharmaceuticals; the quest for total synthesis of natural products fueled development of methodologies for organic synthesis; and their biosynthesis presented unprecedented biochemical transformations, expanding our chemo-enzymatic toolkit. Initially, the discovery of small molecules was driven by bioactivity-guided fractionation. However, this approach yielded the frequent rediscovery of already known metabolites. As a result, focus shifted to identifying novel scaffolds through either structure-first methods or genome mining, relegating function as a secondary concern. Over the past two decades, the laboratory of Jon Clardy has taken an alternative route and focused on an ecology-driven, function-first approach in pursuit of uncovering bacterial small molecules with biological activity. In this review, we highlight several examples that showcase this ecology-first approach. Though the highlighted systems are diverse, unifying themes are (1) to understand how microbes interact with their host or environment, (2) to gain insights into the environmental roles of microbial metabolites, and (3) to explore pharmaceutical potential from these ecologically relevant metabolites.Chromophores based on the para-hydroxycinnamate moiety are widespread in the natural world, including as the photoswitching unit in photoactive yellow protein and as a sunscreen in the leaves of plants. Here, photodetachment action spectroscopy combined with frequency- and angle-resolved photoelectron imaging is used to fingerprint the excited-state dynamics over the first three bright action-absorption bands in the methyl ester anions (pCEs-) of deprotonated para-coumaric acid at a temperature of ∼300 K. The excited states associated with the action-absorption bands are classified as resonances because they are situated in the detachment continuum and are open to autodetachment. The frequency-resolved photoelectron spectrum for pCEs- indicates that all photon energies over the S1(ππ*) band lead to similar vibrational autodetachment dynamics. The S2(nπ*) band is Herzberg-Teller active and has comparable brightness to the higher lying 21(ππ*) band. The frequency-resolved photoelectron spectrum over the S2(nπ*)onic state.A hydrogen bond (HB) is an essential interaction in countless phenomena, regulating the chemistry of life. HBs are characterized by two features, strength and directionality, with a high degree of heterogeneity across different chemical groups. These characteristics are dependent on the electronic configuration of the atoms involved in the interaction, which, in turn, is influenced strongly by the local molecular environment. Studies based on the analysis of HB in the solid phase, such as X-ray crystallography, suffer from significant biases due to packing forces. These will tend to better describe strong HBs at the expenses of weak ones, which will be either distorted or under-represented. Using quantum mechanics (QM), we calculated interaction energies for about a hundred acceptors and donors in a rigorously defined set of geometries. We performed 180,000 independent QM calculations, covering all relevant angular components, mapping strength and directionality in a context free from external biases, with both single-site and cooperative HBs. By quantifying directionality, we show that there is no correlation with strength; therefore, these two components need to be addressed separately. Results demonstrate that there are very strong HB acceptors (e.g., dimethyl sulfoxide) with nearly isotropic interactions and weak ones (e.g., thioacetone) with a sharp directional profile. Similarly, groups can have comparable directional propensity but be very distant in the strength spectrum (e.g., thioacetone and pyridine). Results provide a new perspective on the way HB directionality is described, with implications for biophysics and molecular recognition that ultimately can influence chemical biology, protein engineering, and drug design.The aim of this work is to describe the molecular inclusion of chlordecone with α-, β-, and γ-cyclodextrin in aqueous solution using quantum mechanics. The guest-host complexes of chlordecone and cyclodextrins are modeled in aqueous solution using the multiple minima hypersurface methodology with a PM6-D3H4X semiempirical Hamiltonian, and the lowest energy minima obtained are reoptimized using the M06-2X density functional and the intermolecular interactions described using quantum theory of atoms in molecules (QTAIM). The studied complexes are classified according to the degree of inclusion, namely, total occlusion, partial occlusion, and external interaction. More stable complexes are obtained when γ-CD is used as the host molecule. The interactions characterized through QTAIM analysis are all of electrostatic nature, predominantly of dispersive type. In this work, a method based on the counterpoise correction is also discussed to mitigate the basis set superposition error in density functional theory calculations when using an implicit solvation model.Guided by LC-MS/MS molecular networking-based metabolomics and cytotoxic activity, two new discorhabdin-type alkaloids, tridiscorhabdin (1) and didiscorhabdin (2), were isolated from the sponge Latrunculia biformis, collected from the Weddell Sea (Antarctica) at -291 m depth. Their structures were established by HRESIMS, NMR, [α]D, and ECD data coupled with DFT calculations. Both compounds bear a novel C-N bridge (C-1/N-13) between discorhabdin monomers, and 1 represents the first trimeric discorhabdin molecule isolated from Nature. Tridiscorhabdin (1) exhibited strong cytotoxic activity against the human colon cancer cell line HCT-116 (IC50 value 0.31 μM).Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.Using wave function (WF) in density functional theory (DFT) embedding methods provides a framework for performing localized, high-accuracy WF calculations on a system, while not incurring the full computational cost of the WF calculation on the full system. To effectively partition a system into localized WF and DFT subsystems, we utilize the Huzinaga level-shift projection operator within an absolutely localized basis. In this work, we study the ability of the absolutely localized Huzinaga level-shift projection operator method to study complex WF and DFT partitions, including partitions between multiple covalent bonds, a double bond, and transition-metal-ligand bonds. We find that our methodology can accurately describe all of these complex partitions. Additionally, we study the robustness of this method with respect to the WF method, specifically where the embedded systems were described using a multiconfigurational WF method. We found that the method is systematically improvable with respect to both the number of atoms in the WF region and the size of the basis set used, with energy errors less than 1 kcal/mol. Additionally, we calculated the adsorption energy of H2 to a model of an iron metal-organic framework (Fe-MOF-74) to within 1 kcal/mol compared to CASPT2 calculations performed on the full model while incurring only a small fraction of the full computational cost. This work demonstrates that the absolutely localized Huzinaga level-shift projection operator method is applicable to very complex systems with difficult electronic structures.Structure-based stabilization of protein-protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.
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