Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods

Health benefits of dietary phytochemicals have been suggested in recent years. Among 1000s of different compounds, Betalains, which occur in vegetables of the Cariophyllalae order (cactus pear fruits and red beet), have been considered because of reducing power and potential to affect redox-modulated cellular processes. The antioxidant power of Betalains is strictly due to the dissociation rate of the acid moieties present in all the molecules of this family of phytochemicals. Experimentally, only the pK a values of betanin were determined. Recently, it was evidenced it was evidenced as the acid dissociation, at different environmental pHs, affects on its electron-donating capacity, and further on its free radical scavenging power. The identical correlation was studied on another Betalains family compound, Betalamic Acid. Experimental evidences showed that the free radical scavenging capacity of this compound drastically decreases at pH > 5, but pK a values were experimentally not measured. With the aim to justify the Betalamic Acid behavior as free radical scavenger, in this paper we tried to predict in silico the pK a values by means different approaches. Starting from the known experimental pK as of acid compounds, both phytochemicals and small organic, two empirical approaches and quantum-mechanical calculation were compared to give reliable prediction of the pK as of Betalamic Acid. Results by means these computational approaches are consistent with the experimental evidences. As shown herein, in silico, the totally dissociated species, at the experimental pH > 5 in solution, is predominant, exploiting the higher electron-donating capability (HOMO energy). Therefore, the computational estimated pK a values of Betalamic Acid resulted very reliable

Initial Steps of Thermal Decomposition of Dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate Crystals from Quantum Mechanics

Dihydroxylammonium 5,5?-bistetrazole-1,1?-diolate (TKX-50) is a recently synthesized energetic material (EM) with most promising performance, including high energy content, high density, low sensitivity, and low toxicity. TKX-50 forms an ionic crystal in which the unit cell contains two bistetrazole dianions {c-((NO)N3C)-[c-(CN3(NO)], formal charge of ?2} and four hydroxylammonium (NH3OH)+ cations (formal charge of +1). We report here quantum mechanics (QM)-based reaction studies to determine the atomistic reaction mechanisms for the initial decompositions of this system. First we carried out molecular dynamics simulations on the periodic TKX-50 crystal using forces from density functional based tight binding calculations (DFTB-MD), which finds that the chemistry is initiated by proton transfer from the cation to the dianion. Continuous heating of this periodic system leads eventually to dissociation of the protonated or diprotonated bistetrazole to release N2 and N2O. To refine the mechanisms observed in the periodic DFTB-MD, we carried out finite cluster quantum mechanics studies (B3LYP) for the unimolecular decomposition of the bistetrazole. We find that for the bistetrazole dianion, the reaction barrier for release of N2 is 45.1 kcal/mol, while release of N2O is 72.2 kcal/mol. However, transferring one proton to the bistetrazole dianion decreases the reaction barriers to 37.2 kcal/mol for N2 release and 59.5 kcal/mol for N2O release. Thus, we predict that the initial decompositions in TKX-50 lead to N2 release, which in turn provides the energy to drive further decompositions. On the basis of this mechanism, we suggest changes to make the system less sensitive while retaining the large energy release. This may help improve the synthesis strategy of developing high nitrogen explosives with further improved performance

Tailor-Made Molecularly Imprinted Polymer for Selective Recognition of the Urinary Tumor Marker Pseudouridine

Pseudouridine (?) is an important urinary cancer biomarker, especially in human colorectal cancer (CRC). Disclosed herein is the first ? molecularly imprinted polymer (?-MIP) material obtained from tailor-engineered functional monomers. The resulting MIP imprint exhibits a remarkable imprinting factor greater than 70. It is successfully used for the selective recognition of ? in spiked human urine. This selective functionalized material opens the route to the development of inexpensive disposable chemosensors for noninvasive CRC diagnosis and prognosis

On Predicting Mössbauer Parameters of Iron-Containing Molecules with Density-Functional Theory

The performance of six frequently used density functional theory (DFT) methods (RPBE, OLYP, TPSS, B3LYP, B3LYP*, and TPSSh) in the prediction of Mössbauer isomer shifts(δ) and quadrupole splittings (ΔEQ) is studied for an extended and diverse set of Fe complexes. In addition to the influence of the applied density functional and the type of the basis set, the effect of the environment of the molecule, approximated with the conducting-like screening solvation model (COSMO) on the computed Mössbauer parameters, is also investigated. For the isomer shifts the COSMO-B3LYP method is found to provide accurate δ values for all 66 investigated complexes, with a mean absolute error (MAE) of 0.05 mm s–1 and a maximum deviation of 0.12 mm s–1. Obtaining accurate ΔEQ values presents a bigger challenge; however, with the selection of an appropriate DFT method, a reasonable agreement can be achieved between experiment and theory. Identifying the various chemical classes of compounds that need different treatment allowed us to construct a recipe for ΔEQ calculations; the application of this approach yields a MAE of 0.12 mm s–1 (7% error) and a maximum deviation of 0.55 mm s–1 (17% error). This accuracy should be sufficient for most chemical problems that concern Fe complexes. Furthermore, the reliability of the DFT approach is verified by extending the investigation to chemically relevant case studies which include geometric isomerism, phase transitions induced by variations of the electronic structure (e.g., spin crossover and inversion of the orbital ground state), and the description of electronically degenerate triplet and quintet states. Finally, the immense and often unexploited potential of utilizing the sign of the ΔEQ in characterizing distortions or in identifying the appropriate electronic state at the assignment of the spectral lines is also shown

Initial Decomposition Reactions of Bicyclo-HMX [BCHMX or cis

We investigated the initial chemical reactions of BCHMX [cis-1,3,4,6-tetranitrooctahydroimidazo-[4,5-d]imidazole] with the following procedure. First we used density functional theory molecular dynamics simulations (DFT-MD) on the periodic crystal to discover the initial reaction steps. This allowed us to determine the most important reactions through DFT-MD simulations at high temperatures. Then we started with the midpoint of the reaction (unimolecular or bimolecular) from the DFT-MD and carried out higher quality finite cluster DFT calculations to locate the true transition state of the reaction, followed by calculations along the reaction path to determine the initial and final states. We find that for the noncompressed BCHMX the nitro-aci isomerization reaction occurs earlier than the NO2-releasing reaction, while for compressed BCHMX intermolecular hydrogen-transfer and bimolecular NO2-releasing reactions occur earlier than the nitrous acid (HONO)-releasing reaction. At high pressures, the initial reaction involves intermolecular hydrogen transfer rather than intramolecular hydrogen transfer, and the intermolecular hydrogen transfer decreases the reaction barrier for release of NO2 by ∼7 kcal/mol. Thus, the HONO-releasing reaction takes place more easily in compressed BCHMX. We find that this reaction barrier is 10 kcal/mol lower than the unimolecular NO2 release and ∼3 kcal/mol lower than the bimolecular NO2 release. This rationalizes the origin of the higher sensitivity of BCHMX compared to RDX (1,3,5-trinitrohexahydro-1,3,5-triazine) and HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine). We suggest changes in BCHMX that might help decrease the sensitivity by avoiding the intermolecular hydrogen-transfer and HONO-releasing reaction