Influenza A virus polymerase acidic protein E23G/K substitutions weaken key baloxavir drug-binding contacts with minimal impact on replication and transmission.

Baloxavir marboxil (BXM) is approved for treating uncomplicated influenza. The active metabolite baloxavir acid (BXA) inhibits cap-dependent endonuclease activity of the influenza virus polymerase acidic protein (PA), which is necessary for viral transcription. Treatment-emergent E23G or E23K (E23G/K) PA substitutions have been implicated in reduced BXA susceptibility, but their effect on virus fitness and transmissibility, their synergism with other BXA resistance markers, and the mechanisms of resistance have been insufficiently studied. Accordingly, we generated point mutants of circulating seasonal influenza A(H1N1)pdm09 and A(H3N2) viruses carrying E23G/K substitutions. Both substitutions caused 2- to 13-fold increases in the BXA EC50. EC50s were higher with E23K than with E23G and increased dramatically (138- to 446-fold) when these substitutions were combined with PA I38T, the dominant BXA resistance marker. E23G/K-substituted viruses exhibited slightly impaired replication in MDCK and Calu-3 cells, which was more pronounced with E23K. In ferret transmission experiments, all viruses transmitted to direct-contact and airborne-transmission animals, with only E23K+I38T viruses failing to infect 100% of animals by airborne transmission. E23G/K genotypes were predominantly stable during transmission events and through five passages in vitro. Thermostable PA-BXA interactions were weakened by E23G/K substitutions and further weakened when combined with I38T. In silico modeling indicated this was caused by E23G/K altering the placement of functionally important Tyr24 in the endonuclease domain, potentially decreasing BXA binding but at some cost to the virus. These data implicate E23G/K, alone or combined with I38T, as important markers of reduced BXM susceptibility, and such mutants could emerge and/or transmit among humans.

Trapping and thermal migration of the first- and second-row atoms in Ar, Kr and Xe crystals.

Trapping and temperature-induced migration (TIM) of the first- and second-row atoms A from H to Ne in the face-centered cubic rare gas RG = Ar, Kr and Xe crystals are investigated within the classical crystal model parameterized by the empirically modified pairwise potentials. New ab initio coupled cluster A-RG potentials computed in a uniform way for all the atoms A are used to represent the atom-crystal interactions. Absolute and relative stabilities of the substitutional and interstitial trapping sites, their structures, interstitial migration pathways, related activation energies and rough estimates of the TIM rates are obtained. The isotropic model, which neglects non-zero atomic electronic orbital momentum, reveals that migration of interstitial atoms along the network of conjugated fcc octahedral voids is the generic case for atomic mobility. Anisotropic interactions with a crystal inherent to P-state atoms B, C, O and F are accounted for using the non-relativistic diatomics-in-molecule method. Depending on its sign, interaction anisotropy can alter the structures of interstitial trapping sites and transition states remarkably. This, in turn, can dramatically affect the TIM rates. Comparison with reliable experimental data available for oxygen and hydrogen indicates a systematic overestimation of the measured activation energies, by 30% at worst. A comprehensive literature review accomplished for other atoms reveals a lack of information on the TIM processes and rates, though makes it possible to verify a part of the present results on the trapping site energies and structures.

The Role of Bond Functions in Describing Intermolecular Electron Correlation for Van der Waals Dimers: A Study of (CH4)2 and Ne2.

We present a study of the intermolecular interactions in van der Waals complexes of methane and neon dimers within the framework of the CCSD method. This approach was implemented and applied to calculate and examine the behavior of the contracted two-particle reduced density matrix (2-RDM). It was demonstrated that the region near the minimum of the two-particle density matrix correlation part, corresponding to the primary bulk of the Coulomb hole contribution, exerts a significant influence on the dispersion interaction energetics of the studied systems. As a result, the bond functions approach was applied to improve the convergence performance for the intermolecular correlation energy results with respect to the size of the atomic basis. For this, substantial acceleration was achieved by introducing an auxiliary basis of bond functions centered on the minima of the 2-RDM. For both methane and neon dimers, this general conclusion was confirmed with a series of CCSD calculations for the 2-RDM and the correlation energies.

Chemistry42: An AI-Driven Platform for Molecular Design and Optimization.

Chemistry42 is a software platform for de novo small molecule design and optimization that integrates Artificial Intelligence (AI) techniques with computational and medicinal chemistry methodologies. Chemistry42 efficiently generates novel molecular structures with optimized properties validated in both in vitro and in vivo studies and is available through licensing or collaboration. Chemistry42 is the core component of Insilico Medicine's Pharma.ai drug discovery suite. Pharma.ai also includes PandaOmics for target discovery and multiomics data analysis, and inClinico─a data-driven multimodal forecast of a clinical trial's probability of success (PoS). In this paper, we demonstrate how the platform can be used to efficiently find novel molecular structures against DDR1 and CDK20.

Antibacterial activity of noscapine analogs.

The antibacterial properties of close noscapine analogs have not been previously reported. We used our pDualrep2 double-reporter High Throughput Screening (HTS) platform to identify a series of noscapine derivatives with promising antibacterial activity. The platform is based on RPF (SOS-response/DNA damage) and Katushka2S (inhibition of translation) proteins and simultaneously provides information on antibacterial activity and the mechanism of action of small-molecule compounds against E. coli. The most potent compound exhibited an MIC of 13.5 µM(6.25 µg/ml) and a relatively low cytotoxicity against HEK293 cells (CC50 = 71 µM, selectivity index: ~5.5). Some compounds from this series induced average Katushka2S reporter signals, indicating inhibition of translation machinery in the bacteria; however, these compounds did not attenuate translation in vitro in a luciferase-based translation assay. The most effective compounds did not significantly arrest the mitotic cycle in HEK293 cells, in contrast to the parent compound in a flow cytometry assay. Several molecules showed activity against clinically relevant gram-negative and gram-positive bacterial strains. Compounds from the discovered series can be reasonably regarded as good templates for further development and evaluation.

Modeling of the thermal migration mechanisms of atomic oxygen in Ar, Kr, and Xe crystals.

Accommodation and migration of the ground-state (2s22p4 3P) oxygen atom in the ideal Ar, Kr, and Xe rare gas crystals are investigated using the classical model. The model accounts for anisotropy of interaction between guest and host atoms, spin-orbit coupling, and lattice relaxation. Interstitial and substitutional accommodations are found to be the only thermodynamically stable sites for trapping atomic oxygen. Mixing of electronic states coupled to lattice distortions justifies that its long-range thermal migration follows the adiabatic ground-state potential energy surface. Search for the migration paths reveals a common direct mechanism for interstitial diffusion. Substitutional atoms are activated by the point lattice defects, whereas the direct guest-host exchange meets a higher activation barrier. These three low-energy migration mechanisms provide plausible interpretation for multiple migration activation thresholds observed in Kr and Xe free-standing crystals, confirmed by reasonable agreement between calculated and measured activation energies. An important effect of interaction anisotropy and a minor role of spin-orbit coupling are emphasized.

Identification of pyrrolo-pyridine derivatives as novel class of antibacterials.

A series of 5-oxo-4H-pyrrolo[3,2-b]pyridine derivatives was identified as novel class of highly potent antibacterial agents during an extensive large-scale high-throughput screening (HTS) program utilizing a unique double-reporter system-pDualrep2. The construction of the reporter system allows us to perform visual inspection of the underlying mechanism of action due to two genes-Katushka2S and RFP-which encode the proteins with different imaging signatures. Antibacterial activity of the compounds was evaluated during the initial HTS round and subsequent rescreen procedure. The most active molecule demonstrated a MIC value of 3.35 µg/mL against E. coli with some signs of translation blockage (low Katushka2S signal) and no SOS response. The compound did not demonstrate cytotoxicity in standard cell viability assay. Subsequent structural morphing and follow-up synthesis may result in novel compounds with a meaningful antibacterial potency which can be reasonably regarded as an attractive starting point for further in vivo investigation and optimization.

Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA.

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.

Accommodation of a dimer in an Ar-like lattice: exploring the generic structural motifs.

A global optimization strategy is applied to Lennard-Jones models describing the stable trapping sites of a dimer in the face-centered cubic Ar-like lattice. Effective volumes of the trapping sites, quantified as the number of host atoms dislodged from the lattice, are mapped onto the parameter space defined by the strength and range of the dimer interaction potentials. The two models considered differ in the host-guest interaction and give very different maps that reflect the effect of local lattice relaxation. A hierarchical complete-linkage clustering technique is applied to identify generic structural types of the dimer accommodations. The dominant types found and enlisted maintain the symmetry of the isolated dimer and possess high tetrahedral and octahedral symmetry of the host environment with respect to the dimer atoms or center and can be roughly classified as the "whole" or "per atom" dimer accommodations. The results are compared to the analysis of the analogous model for trapped atoms and realistic model for trapped alkaline-earth metal dimers. Implications for matrix isolation spectroscopy are discussed.

Stable axially symmetric atomic impurity in an fcc solid-Ba in rare gases.

Closed-shell metal atoms in rare gas solids tend to occupy highly symmetric polyhedral crystal sites, as follows from the generic triplet Jahn-Teller splitting of the S → P excitation bands and complies with the isotropic nature of the dispersion forces. Atypical 2 + 1 Jahn-Teller splitting inherent to axially symmetric sites observed recently for Ba atoms has been therefore interpreted as the defect accommodation. By modeling the structure, stability, and spectra of the Ba atom in the face-centered cubic rare gas crystals, we identify thermodynamically stable crystal site of axial C3v symmetry that explains experimental observations. We also demonstrate the dramatic effect of the interaction anisotropy on the trapping site structure and stability for an excited P-state atom. Our results provide strong evidence for stable axially symmetric accommodation of isotropic impurity in a close-packed lattice.

Ab initio interaction potentials of the Ba, Ba+ complexes with Ar, Kr, and Xe in the lowest excited states.

The complexes of the Ba atom and Ba+ cation with the rare gas atoms Ar, Kr, and Xe in the states associated with the 6s → 5d, 6p excitations are investigated by means of the multireference configuration interaction techniques. Scalar relativistic potentials are obtained by the complete basis limit extrapolation through the sequence of aug-cc-pwCVnZ basis sets with the cardinal numbers n = Q, T, 5, combined with the suitable effective core potentials and benchmarked against the coupled cluster with singles, doubles, and non-iterative triples calculations and the literature data available for selected electronic states. Spin-orbit coupling is taken into account by means of the state-interacting multireference configuration interaction calculations performed for the Breit-Pauli spin-orbit Hamiltonian. The results show weak spin-orbit coupling between the states belonging to distinct atomic multiplets. General trends in the interaction strength and long-range anisotropy along the rare gas series are discussed. Vibronic spectra of the Ba and Ba+ complexes in the vicinity of the 1S → 1P° and 2S → 2P° atomic transitions and diffusion cross sections of the Ba(1S0, 3DJ) atom in high-temperature rare gases are calculated. Comparison with available experimental data shows that multireference calculations tend to underestimate the interaction strength for excited complexes.

Modeling of Manganese Atom and Dimer Isolated in Solid Rare Gases: Structure, Stability, and Effect on Spin Coupling.

Structures and energies of the trapping sites of manganese atom and dimer in solid Ar, Kr, and Xe are investigated within the classical model, which balances local distortion and long-range crystal order of the host and provides a means to estimate the relative site stabilities. The model is implemented with the additive pairwise potential field based on the ab initio and best empirical interatomic potential functions. In agreement with experiment, Mn single substitution (SS) and tetrahedral vacancy (TV) occupation are identified as stable for Ar and Kr, whereas the SS site is only found for Xe. Stable trapping sites of the weakly bound Mn2 dimer are shown to be the mergers of SS and/or TV atomic sites. For Ar, (SS + SS) and (TV + TV) sites are close in energy, whereas (SS + TV) site lies higher. The (SS + SS) accommodation is identified as the only stable site in Kr and Xe at low energies. The results are compared with the resonance Raman, electron spin resonance, and absorption spectroscopy data. Reproducing the numbers of stable sites, the calculations tend to underestimate the matrix effect on the dimer vibrational frequency and spin-spin coupling constant. Nonetheless, the level of agreement is found to be informative for tentative assignments of the complex features seen in Mn2 matrix isolation spectroscopy.

Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives.

A set of novel selenohydantoins were synthesized via a convenient and versatile approach involving the reaction of isoselenocyanates with various amines. We also revealed an unexpected Z→E isomerization of pyridin-2-yl-substituted selenohydantoins in the presence of Cu(2+) cations. The detailed mechanism of this transformation was suggested on the basis of quantum-chemical calculations, and the key role of Cu(2+) was elucidated. The obtained compounds were subsequently evaluated against a panel of different cancer cell lines. As a result, several molecules were identified as promising micromolar hits with good selectivity index. Instead of analogous thiohydantoins, which have been synthesized previously, selenohydantoins demonstrated a relatively high antioxidant activity comparable (or greater) to the reference molecule, Ebselen, a clinically approved drug candidate. The most active compounds have been selected for further biological trials.

Reaction rate constant for radiative association of CF(.).

Reaction rate constants and cross sections are computed for the radiative association of carbon cations (C(+)) and fluorine atoms (F) in their ground states. We consider reactions through the electronic transition 1(1)Π â†’ X(1)Σ(+) and rovibrational transitions on the X(1)Σ(+) and a(3)Π potentials. Semiclassical and classical methods are used for the direct contribution and Breit-Wigner theory for the resonance contribution. Quantum mechanical perturbation theory is used for comparison. A modified formulation of the classical method applicable to permanent dipoles of unequally charged reactants is implemented. The total rate constant is fitted to the Arrhenius-Kooij formula in five temperature intervals with a relative difference of <3%. The fit parameters will be added to the online database KIDA. For a temperature of 10-250 K, the rate constant is about 10(-21) cm(3) s(-1), rising toward 10(-16) cm(3) s(-1) for a temperature of 30,000 K.

Quantum-assisted fragment-based automated structure generator (QFASG) for small molecule design: an in vitro study.

Introduction: The significance of automated drug design using virtual generative models has steadily grown in recent years. While deep learning-driven solutions have received growing attention, only a few modern AI-assisted generative chemistry platforms have demonstrated the ability to produce valuable structures. At the same time, virtual fragment-based drug design, which was previously less popular due to the high computational costs, has become more attractive with the development of new chemoinformatic techniques and powerful computing technologies. Methods: We developed Quantum-assisted Fragment-based Automated Structure Generator (QFASG), a fully automated algorithm designed to construct ligands for a target protein using a library of molecular fragments. QFASG was applied to generating new structures of CAMKK2 and ATM inhibitors. Results: New low-micromolar inhibitors of CAMKK2 and ATM were designed using the algorithm. Discussion: These findings highlight the algorithm's potential in designing primary hits for further optimization and showcase the capabilities of QFASG as an effective tool in this field.

Formation of the SiP radical through radiative association.

Formation of the SiP radical through radiative association of Si((3)P) and P((4)S) atoms is studied using classical and quantum dynamics. Rate coefficients for formation in the two lowest doublet states and the two lowest quartet states are calculated for T = 10-20,000 K. Breit-Wigner theory is used to properly account for contribution from quantum mechanical resonances.

Quantum computing for near-term applications in generative chemistry and drug discovery.

In recent years, drug discovery and life sciences have been revolutionized with machine learning and artificial intelligence (AI) methods. Quantum computing is touted to be the next most significant leap in technology; one of the main early practical applications for quantum computing solutions is predicted to be in quantum chemistry simulations. Here, we review the near-term applications of quantum computing and their advantages for generative chemistry and highlight the challenges that can be addressed with noisy intermediate-scale quantum (NISQ) devices. We also discuss the possible integration of generative systems running on quantum computers into established generative AI platforms.

The Hitchhiker's Guide to Deep Learning Driven Generative Chemistry.

This microperspective covers the most recent research outcomes of artificial intelligence (AI) generated molecular structures from the point of view of the medicinal chemist. The main focus is on studies that include synthesis and experimental in vitro validation in biochemical assays of the generated molecular structures, where we analyze the reported structures' relevance in modern medicinal chemistry and their novelty. The authors believe that this review would be appreciated by medicinal chemistry and AI-driven drug design (AIDD) communities and can be adopted as a comprehensive approach for qualifying different research outcomes in AIDD.