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Although seeking to develop a general and accurate binding free energy calculation method for protein–protein and protein–ligand interactions has been a continuous effort for decades, only limited successes have been obtained so far. Here, we report the development of a metadynamics-based procedure that calculates Dissociation Free Energy (DFE) and its application to 19 non-congeneric protein–protein complexes and hundreds of protein–ligand complexes covering eight targets. We achieved very high correlations in comparison to experimental binding free energies for these diverse sets of systems, demonstrating the generality and accuracy of the method. Since structures of most proteins are available owing to the recent success of prediction by artificial intelligence, a general free energy method such as DFE, combined with other methods, can make structure-based drug design a widely viable and reliable solution to develop both traditional small molecule drugs and biologic drugs as well as PROTACS. [ABSTRACT FROM AUTHOR]

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2 nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein–ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile. [ABSTRACT FROM AUTHOR]

Details the design of inhibitors for human carbonic anhydrase II using combinatorial small molecule growth algorithm. Principle of the COmbiMoG algorithm; Computational methodology involved; Potential applications of the technique in drug development.

Proposes a de novo molecular design method, the SMoG program, based on simple, fast and accurate free energy estimates. Presentation of suggestions for ligands to Src SH3 domain and CD4; General outline for ligand design; Case studies in molecular design.

Samples of ZrO2 ceramics with different concentrations of impurity titanium ions were synthesized by mixing zirconium and titanium oxide powders in different mass ratios. The X-ray diffraction analysis was used to determine the phase composition, lattice parameters, and crystallite size of the ceramics with varying dopant concentrations. Upon irradiation of the samples with 220 MeV Xe ions to a fluence of 1010 ions/cm2, a decrease in the intensity of the pulsed cathodoluminescence band at 2.5 eV was observed. Additionally, ion irradiation resulted in the emergence of a new thermoluminescence peak at 450–650 K attributed to radiation-induced traps of charge carriers. Further analysis revealed that the thermoluminescence curves of samples irradiated with electrons and ions comprise a superposition of several elementary peaks. Notably, a complex non-monotonic dependence of cathodo- and thermoluminescence intensity on titanium concentration was observed, suggesting the influence of concentration quenching and the presence of tunneling transitions. [ABSTRACT FROM AUTHOR]

Gd3+ and Sm3+ co-activation, the effect of cation substitutions and the creation of cation vacancies in the scheelite-type framework are investigated as factors influencing luminescence properties. AgxGd((2−x)/3)−0.3−ySmyEu3+0.3☐(1−2x)/3WO4 (x = 0.50, 0.286, 0.20; y = 0.01, 0.02, 0.03, 0.3) scheelite-type phases (AxGSyE) have been synthesized by a solid-state method. A powder X-ray diffraction study of AxGSyE (x = 0.286, 0.2; y = 0.01, 0.02, 0.03) shows that the crystal structures have an incommensurately modulated character similar to other cation-deficient scheelite-related phases. Luminescence properties have been evaluated under near-ultraviolet (n–UV) light. The photoluminescence excitation spectra of AxGSyE demonstrate the strongest absorption at 395 nm, which matches well with commercially available UV-emitting GaN-based LED chips. Gd3+ and Sm3+ co-activation leads to a notable decreasing intensity of the charge transfer band in comparison with Gd3+ single-doped phases. The main absorption is the 7F0 → 5L6 transition of Eu3+ at 395 nm and the 6H5/2 → 4F7/2 transition of Sm3+ at 405 nm. The photoluminescence emission spectra of all the samples indicate intense red emission due to the 5D0 → 7F2 transition of Eu3+. The intensity of the 5D0 → 7F2 emission increases from ~2 times (x = 0.2, y = 0.01 and x = 0.286, y = 0.02) to ~4 times (x = 0.5, y = 0.01) in the Gd3+ and Sm3+ co-doped samples. The integral emission intensity of Ag0.20Gd0.29Sm0.01Eu0.30WO4 in the red visible spectral range (the 5D0 → 7F2 transition) is higher by ~20% than that of the commercially used red phosphor of Gd2O2S:Eu3+. A thermal quenching study of the luminescence of the Eu3+ emission reveals the influence of the structure of compounds and the Sm3+ concentration on the temperature dependence and behavior of the synthesized crystals. Ag0.286Gd0.252Sm0.02Eu0.30WO4 and Ag0.20Gd0.29Sm0.01Eu0.30WO4, with the incommensurately modulated (3 + 1)D monoclinic structure, are very attractive as near-UV converting phosphors applied as red-emitting phosphors for LEDs. [ABSTRACT FROM AUTHOR]

Abstract Solid solution of Ca 10.5–1.5 x Yb x (PO 4) 7 (0 ≤ x ≤ 1) was synthesized in the β -Са 3 (РО 4) 2 -type structure by a standard solid-state method. Second-harmonic generation, differential scanning calorimetry, and dielectric measurements showed the presence of a reversible first-order phase transition of ferroelectric type between the room-temperature polar R 3 c structure to centrosymmetry. The temperature of the phase transition decreases from 1203 K for x = 0 to 788 K for x = 1, while the second-harmonic generation response decreases from 1.4 to 0.17 α-SiO 2 powder standard units. The luminescence spectra of Ca 10.5–1.5 x Yb x (PO 4) 7 point to two structural Yb3+ positions in full agreement with the structural data. The intensity of the luminescence emission line at ∼975 nm due to the 2F 5/2 → 2F 7/2 transition reaches the maximum at x = 0.667 in Ca 10.5–1.5 x Yb x (PO 4) 7. The Yb3+ luminescence spectra studied as a function of the chemical composition 0 < x ≤ 1 are compared with the corresponding crystallographic data obtained from the powder diffraction of both X-Ray and synchrotron radiation. Although the overwhelming majority of the Yb3+ cations are located in the pseudosymmetry in M 5 position, their smaller number is located in an acentric manner in M 1 and M 2. A structural mechanism for the transition between the polar (ferroelectric, space group R 3 c) and centrosymmetric (paraelectric, space group R- 3 c) phases is proposed. Graphical abstract Image 1 Highlights • Whitlockite-type Ca 10.5–1.5 x Yb x (PO 4) 7 (0 < x ≤ 1) phosphates were designed. • There is reversible ferroelectric phase transition in temperature range 788–1203 K have been found. • Ca 10.5–1.5 x Yb x (PO 4) 7 exhibit intense broad bands luminescence in the NIR range. • This work provides exploration Ca 10.5–1.5 x Yb x (PO 4) 7 for medicine applications laser materials. [ABSTRACT FROM AUTHOR]

Abstract: Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension. [Copyright &y& Elsevier]

Abstract: Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC50 of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension. [Copyright &y& Elsevier]

Abstract: Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC50 of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension. [Copyright &y& Elsevier]

Summary Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors. [ABSTRACT FROM AUTHOR]