Low-energy Conformations Research Articles

Streamlined Protein-Protein Interface Loop Mimicry.

Cyclic peptides comprising endocyclic organic fragments, "cyclo-organopeptides", can be probes for perturbing protein-protein interactions (PPIs). Finding loop mimics is difficult because of high conformational variability amongst targets. Backbone Matching (BM), introduced here, helps solve this problem in the illustrative cases by facilitating efficient evaluation of virtual cyclo-organopeptide core-structure libraries. Thus, 86 rigid organic fragments were selected to build a library of 602 cyclo-organopeptides comprising Ala and organic parts: "cyclo-{-(Ala)n -organo-}". The central hypothesis is "hit" library members have accessible low energy conformers corresponding to backbone structures of target protein loops, while library members which cannot attain this conformation are probably unworthy of further evaluation. BM thereby prioritizes candidate loop mimics, so that less than 10 cyclo-organopeptides are needed to be prepared to find leads for two illustrative PPIs: iNOS ⋅ SPSB2, and uPA ⋅ uPAR.

Streamlined Protein‐Protein Interface Loop Mimicry

AbstractCyclic peptides comprising endocyclic organic fragments, “cyclo‐organopeptides”, can be probes for perturbing protein‐protein interactions (PPIs). Finding loop mimics is difficult because of high conformational variability amongst targets. Backbone Matching (BM), introduced here, helps solve this problem in the illustrative cases by facilitating efficient evaluation of virtual cyclo‐organopeptide core‐structure libraries. Thus, 86 rigid organic fragments were selected to build a library of 602 cyclo‐organopeptides comprising Ala and organic parts: “cyclo‐{‐(Ala)n‐organo‐}”. The central hypothesis is “hit” library members have accessible low energy conformers corresponding to backbone structures of target protein loops, while library members which cannot attain this conformation are probably unworthy of further evaluation. BM thereby prioritizes candidate loop mimics, so that less than 10 cyclo‐organopeptides are needed to be prepared to find leads for two illustrative PPIs: iNOS ⋅ SPSB2, and uPA ⋅ uPAR.

Missing a "Missing Self" Mechanism: Modeling and Detection of Ly49 Expression in Canine NK Cells.

NK cells are a key focus in immuno-oncology, based on their ability to eliminate malignant cells without prior sensitization. Dogs are valuable models for translational immunotherapy studies, especially for NK cells, where critical species differences exist between mice and humans. Given that the mechanism for recognition of "self" by canine NK cells is currently unknown, we sought to evaluate expression of Ly49 in canine NK cells using in silico and high-throughput techniques. We interrogated the identified polymorphism/mutation in canine Ly49 and assessed the potential impact on structure using computational modeling of three-dimensional protein structure and protein-protein docking of canine Ly49 with MHC class I (MHC-I). Bulk and single-cell RNA-sequencing analysis was performed to detect gene expression of Ly49/KLRA1 in resting and activated NK cells. Tertiary protein structure demonstrated significant structural similarity to the known murine system. Molecular docking of canine Ly49 with MHC-I was favorable, converging at a single low-energy conformation. RNA sequencing revealed expression of Ly49/KLRA1 in both resting and activated NK cells and demonstrated almost exclusive expression of the gene in the NK cluster at the single-cell level. Despite prior reports of a mutated, nonfunctional canine Ly49, our data support that the protein product is predicted to bind to MHC-I in a comparable conformation to the murine system and is expressed in canine NK cells with upregulation following activation. Taken together, these data suggest that Ly49 is capable of recognizing MHC-I and therefore regulating NK cell function in dogs.

Phenylpropiolic acid isolated in cryogenic nitrogen and xenon matrices: NIR and UV-induced study.

Phenylpropiolic acid (C6H5C≡CCOOH, PPA) isolated in nitrogen and xenon cryogenic matrices was studied by infrared spectroscopy. The experimental studies were complemented by a series of quantum chemical calculations carried out at the density functional theory (B3LYP) and MP2 levels of theory (with different basis sets). The calculations predicted the existence of two planar PPA conformers, differing in the arrangement of the carboxylic group. The higher-energy trans-PPA conformer has a negligible population in the gas phase at room temperature and was prepared in situ in the N2 cryomatrix through vibrationally-induced rotamerization of the lower-energy cis-PPA conformer, achieved using selective narrowband infrared excitation of the OH stretching coordinate of the latter species. Broadband UV (λ > 235nm) irradiation of matrix-isolated cis-PPA was also undertaken, leading to the observation of cis-PPA → trans-PPA isomerization. No other UV-induced photoreactions were observed. The in situ generated trans-PPA conformer was found to decay back to cis-PPA in the dark by tunneling, and its lifetimes under different experimental conditions were determined. The assignment of the infrared spectra of both conformers is presented, considerably extending the vibrational information available on this molecule.

Small-Molecule Conformer Generators: Evaluation of Traditional Methods and AI Models on High-Quality Data Sets.

Small-molecule conformer generation (SMCG) is an extremely important task in both ligand- and structure-based computer-aided drug design, especially during the hit discovery phase. Recently, a multitude of artificial intelligence (AI) models tailored for SMCG have emerged. Despite developers typically furnishing performance evaluation data upon releasing their AI models, a comprehensive and equitable performance comparison between AI models and conventional methods is still lacking. In this study, we curated a new benchmarking data set comprising 3354 high-quality ligand bioactive conformations. Subsequently, we conducted a systematic assessment of the performance of four widely adopted traditional methods (i.e., ConfGenX, Conformator, OMEGA, and RDKit ETKDG) and five AI models (i.e., ConfGF, DMCG, GeoDiff, GeoMol, and torsional diffusion) in the tasks of reproducing bioactive and low-energy conformations of small molecules. In the former task, the AI models have no advantage, particularly with a maximum ensemble size of 1. Even the best-performing AI model GeoMol is still worse than any of the tested traditional methods. Conversely, in the latter task, the torsional diffusion model shows obvious advantages, surpassing the best-performing traditional method ConfGenX by 26.09 and 12.97% on the COV-R and COV-P metrics, respectively. Furthermore, the influence of force field-based fine-tuning on the quality of the generated conformers was also discussed. Finally, a user-friendly Web server called fastSMCG was developed to enable researchers to rapidly and flexibly generate small-molecule conformers using both traditional and AI methods. We anticipate that our work will offer valuable practical assistance to the scientific community in this field.

Scaffold Matcher: A CMA-ES based algorithm for identifying hotspot aligned peptidomimetic scaffolds.

The design of protein interaction inhibitors is a promising approach to address aberrant protein interactions that cause disease. One strategy in designing inhibitors is to use peptidomimetic scaffolds that mimic the natural interaction interface. A central challenge in using peptidomimetics as protein interaction inhibitors, however, is determining how best the molecular scaffold aligns to the residues of the interface it is attempting to mimic. Here we present the Scaffold Matcher algorithm that aligns a given molecular scaffold onto hotspot residues from a protein interaction interface. To optimize the degrees of freedom of the molecular scaffold we implement the covariance matrix adaptation evolution strategy (CMA-ES), a state-of-the-art derivative-free optimization algorithm in Rosetta. To evaluate the performance of the CMA-ES, we used 26 peptides from the FlexPepDock Benchmark and compared with three other algorithms in Rosetta, specifically, Rosetta's default minimizer, a Monte Carlo protocol of small backbone perturbations, and a Genetic algorithm. We test the algorithms' performance on their ability to align a molecular scaffold to a series of hotspot residues (i.e., constraints) along native peptides. Of the 4 methods, CMA-ES was able to find the lowest energy conformation for all 26 benchmark peptides. Additionally, as a proof of concept, we apply the Scaffold Match algorithm with CMA-ES to align a peptidomimetic oligooxopiperazine scaffold to the hotspot residues of the substrate of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our implementation of CMA-ES into Rosetta allows for an alternative optimization method to be used on macromolecular modeling problems with rough energy landscapes. Finally, our Scaffold Matcher algorithm allows for the identification of initial conformations of interaction inhibitors that can be further designed and optimized as high-affinity reagents.

Conformational particularities of beta-amyloid peptide 25-35

In Alzheimer's disease, beta-amyloid peptide (Ав) plays an important role in the mechanism of neurodegeneration. A small fragment of Лв(25-35) (with the sequence GSNKGAIIGLLM) is regarded to be the functional domain of Лв, responsible for its neurotoxic properties and represents the biological active region of Лв. Conformational analysis of each C-terminal segment of the peptide by the method of molecular mechanics revealed a limited number of most probable conformations and quite clearly helped to clarify what forces stabilize the structures. The obtained results showed that Лв(25-35) energetically has a propensity for adopting alpha-helix conformation of the C-terminal octapeptide segment. A molecular dynamics method was used to build a model of intramolecular mobility in the Лв(25-35) molecule. It was demonstrated that in low-energy conformations, Лв(25-35), the orientation of flexible structures of the N-terminal region with respect to the structures of the C-terminal region is different.

Molecular Dynamics for the Optimal Design of Functionalized Nanodevices to Target Folate Receptors on Tumor Cells.

Atomistic details on the mechanism of targeting activity by biomedical nanodevices of specific receptors are still scarce in the literature, where mostly ligand/receptor pairs are modeled. Here, we use atomistic molecular dynamics (MD) simulations, free energy calculations, and machine learning approaches on the case study of spherical TiO2 nanoparticles (NPs) functionalized with folic acid (FA) as the targeting ligand of the folate receptor (FR). We consider different FA densities on the surface and different anchoring approaches, i.e., direct covalent bonding of FA γ-carboxylate or through polyethylene glycol spacers. By molecular docking, we first identify the lowest energy conformation of one FA inside the FR binding pocket from the X-ray crystal structure, which becomes the starting point of classical MD simulations in a realistic physiological environment. We estimate the binding free energy to be compared with the existing experimental data. Then, we increase complexity and go from the isolated FA to a nanosystem decorated with several FAs. Within the simulation time framework, we confirm the stability of the ligand-receptor interaction, even in the presence of the NP (with or without a spacer), and no significant modification of the protein secondary structure is observed. Our study highlights the crucial role played by the spacer, FA protonation state, and density, which are parameters that can be controlled during the nanodevice preparation step.

IGLOO: An Iterative Global Exploration and Local Optimization Algorithm to Find Diverse Low-Energy Conformations of Flexible Molecules

The exploration of the energy landscape of a chemical system is essential for understanding and predicting its observable properties. In most cases, this is a challenging task due to the high complexity of such landscapes, which often consist of multiple, possibly hierarchical basins that are difficult to locate and thoroughly explore. In this study, we introduce a novel method, called IGLOO (Iterative Global Exploration and Local Optimization), which aims to achieve a more efficient global exploration of the conformational space compared to existing techniques. The method utilizes a tree-based exploration inspired by the Rapidly exploring Random Tree (RRT) algorithm originating from robotics. IGLOO dynamically adjusts its exploration strategy to both homogeneously scan the landscape and focus on promising regions, avoiding redundant exploration. We evaluated IGLOO using models of two polypeptides and compared its performance to the traditional basin-hopping method and a hybrid method that also incorporates the RRT algorithm. We find that IGLOO outperforms both alternative methods in terms of efficiently and comprehensively exploring the molecular conformational space. This approach can be easily generalized to other chemical systems such as molecules on surfaces or crystalline systems.

Detection of a C4 Criegee Intermediate: Fourier-Transform Microwave Spectroscopy of Methacrolein Oxide.

Pure rotational transitions of methacrolein oxide (MACRO) were observed by Fourier-transform microwave spectroscopy. Among the four low-lying conformers existing within an energy window of 3 kcal/mol, only the lowest-energy conformer, the anti-trans conformer, was detected in a discharged jet of a 1,3-diiode-2-methylprop-1-ene and O2 mixture diluted in Ar. Nineteen pure rotational transitions, in the frequency range from 10 to 25 GHz, most of them showing A/E splitting due to the methyl-top internal rotation, were observed and analyzed by the XIAM program, yielding the internal rotation barrier of 559 cm-1, which very well agrees with a theoretically calculated value, 558 cm-1, at the CCSD(T)/cc-pVTZ level of theory.

Structure Elucidation and Interaction Dynamics of MefA-MsrD Efflux Proteins in Streptococcus pneumoniae: Impact on Macrolide Susceptibility.

Macrolides are empirically used to treat bacterial community-acquired pneumonia (CAP). Streptococcus pneumoniae, being the major pathogen responsible for bacterial CAP with high mortality rates, express MefA-MsrD efflux pumps to hinder macrolide susceptibility. Despite its importance, the structural features of the efflux-protein complex and its impact on macrolide susceptibility have not yet been elucidated explicitly. Therefore, in the present study, combining homology, threading, and dynamics approaches, MefA and MsrD proteins in pathogenic S. pneumoniae were modeled. Both membrane (lipid-bilayer) and cytoplasmic (aqueous) environments were considered to simulate the MefA and MsrD proteins in their ideal cellular conditions followed by dynamics analyses. The simulated MefA structure represented a typical major facilitator superfamily protein structure with 13 transmembrane helices. MefA-MsrD interaction via clustering-based docking revealed low-energy conformers with stable intermolecular interactions. The higher clinical MIC value of azithromycin over erythromycin was reflected upon erythromycin eliciting stronger interactions (dissociation constant or ki = ∼52 μM) with the cytoplasmic ATP-binding MsrD than azithromycin (ki = ∼112 μM). The strong (binding energy = -132.1 ± 9.5 kcal/mol) and highly stable (root-mean-square fluctuation < 1.0 Å) physical association between MefA with MsrD was validated and was found to be unaffected by the antibiotic binding. Higher propensity of the macrolides to interact with MsrD than MefA established the importance of the former in macrolide susceptibility. Ours is probably the first report on the structural arrangements in the MefA-MsrD efflux complex and the macrolide susceptibility in S. pneumoniae. This study provides a novel lead for experimental explorations and efflux-pump inhibitor designs.

Structural and vibrational analysis of glycyl-L-phenylalanine and phase transition under high-pressure

The structural and vibrational properties of the glycyl-L-phenylalanine dipeptide were investigated using vibrational spectroscopy (Raman and infrared) and first-principle calculations. Raman spectroscopy measurements were performed between 100 and 3200 cm−1 and infrared spectroscopy from 100 and 3200 cm−1 under ambient conditions. The conformational analysis of the zwitterionic form of the dipeptide was performed using the B3LYP functional, the 6–311++ base set and the Polarizable Continuum Model of solvation, determining the lowest energy conformation and assigning the vibrational modes. The effect of pressure on the glycyl-1-phenylalanine crystal was investigated using the Raman spectroscopy between 0.0 and -7.1 GPa in the spectral region of 100 – 3200 cm−1. As a result, conformational changes around 1.0 GPa were observed in the lattice modes and in some internal modes, showing a reorganization of the molecule in the crystal. In the decompression process, it was observed that the conformational change is reversible and the original Raman spectrum is recoverd.

Theoretical study on hydrogen abstraction reactions from pentane isomers by NO2

The rate constants for the H-abstraction reactions of C5H12 + NO2 are calculated by high-accuracy electronic structure calculations and transition state theory (TST). The investigation includes three pentane isomers, neopentane, n-pentane, and iso-pentane, each of which leads to the formation of three different HONO isomers, namely cis-HONO, trans-HONO, and HNO2. The lowest energy conformers of all relevant species are determined through geometry optimization, frequency analysis, and one-dimensional hindered rotor scanning at the M06-2X/6-311++G(d,p) level of theory, and are further re-optimized using the B2PLYP-D3/cc-pVTZ method. The single point energies of all the reactants, products, and transition states are obtained at the DLPNO-CCSD(T)/CBS level of theory. Traditional transition state theory was employed to derive the rate constants, which were then fitted to obtain the kinetic parameters in the Arrhenius expression. Simulation results show improved performance in ignition delay times and oxidation species prediction, when the calculated reaction rate constants are implemented in the literature n-pentane kinetic models. The results offer enhanced comprehension of the chemistry of C5H12 + NO2, and will aid in the understanding of the mutual reactions of large hydrocarbon fuels and NOx.

AIE‐Active ‘Turn‐On’ Sensors for Highly Selective Detection of Bovine Serum Albumin**

AbstractTetraphenylethylene (TPE)‐based, two molecular ‘Turn‐On’ probes i. e. 4,4′,4′′,4′′′‐(ethene‐1,1,2,2‐tetrayl)tetraphenol (tetrahydroxy‐TPE, coded as: TPE‐1) 4,4′,4′′,4′′′‐(ethene‐1,1,2,2‐tetrayl)tetraaniline and tetraamino‐TPE, coded as: TPE‐2) have been successfully reported for the selective detection of bovine serum albumin (BSA) over its other biological competitors. The BSA sensing has been investigated using UV‐Vis absorption and fluorescence emission spectroscopy, where the fluorescence of probes tetrahydroxy‐TPE and tetra‐amino‐TPE was significantly enhanced in the presence of BSA. The BSA sensing was also characterized by visual eye detection, where a significant color change of probe tetrahydroxy‐TPE and tetra‐amino‐TPE was observed with BSA. The detection limit for BSA was calculated to be 0.2 nM and 1.41 nM for using probes tetrahydroxy‐TPE and tetra‐amino‐TPE, respectively. The binding constant was observed to be1.8×103 M and 1.4×103 M for probes tetrahydroxy‐TPE and tetra‐amino‐TPE, respectively. A molecular docking study is also performed to investigate the detailed interactions between probes tetrahydroxy‐TPE and tetra‐amino‐TPE with BSA. The lowest binding energy conformation for probes tetrahydroxy‐TPE and tetra‐amino‐TPE was found at −8.1 kcal/mol and −8.2 kcal/mol, respectively.

Conformational analysis of carboxylic acid anhydrides: A microwave and computational study

The microwave spectra of four carboxylic acid anhydrides, RCOOCOR′, (R,R′) = (CH3,CF3), (C(CH3)3,CF3), (C6H5, CF3) and (CH3, C(CH3)3), have been observed in a supersonic jet. Calculations at the M06-2X/6-311++G(d,p) and MP2/6-311++G(d,p) levels of theory predict the lowest energy conformations for all four species to be nonplanar cis structures, i.e., conformations in which the C=O groups point in approximately the same direction, but are twisted out of a coplanar orientation. The observed spectra are consistent with these predictions. In addition, for all but the (R,R′) = (CH3, C(CH3)3) species, higher energy nonplanar trans conformers are also predicted, typically within 1–2 kcal/mole the nonplanar cis form. For (R,R′)= (C(CH3)3, CF3), extensive isotopic substitution has enabled a determination of most of the (non-fluorine) heavy atom structural parameters. Excellent agreement with the DFT and MP2 structures was obtained, thus validating the theoretical methods used. A strong correlation is found between the calculated O=C⋯C=O dihedral angle and the average of the vapor phase C=O stretching frequencies of RCOOH and R′COOH.

Discovery of the Elusive Carbonic Acid (HOCOOH) in Space

A quarter century after the detection of the last interstellar carboxylic acid, acetic acid (CH3COOH), we report the discovery of a new one, the cis-trans form of carbonic acid (HOCOOH), toward the Galactic center molecular cloud G+0.693–0.027. HOCOOH stands as the first interstellar molecule containing three oxygen atoms and the third carboxylic acid detected so far in the interstellar medium. Albeit the limited available laboratory measurements (up to 65 GHz), we have also directly identified several pairs of unblended lines in the astronomical data (between 75 and 120 GHz), which allowed us to slightly improve the set of spectroscopic constants. We derive a column density for cis-trans HOCOOH of N = (6.4 ± 0.4) × 1012 cm−2, which yields an abundance with respect to molecular H2 of 4.7 × 10−11. Meanwhile, the extremely low dipole moment (about 15 times lower) of the lower-energy conformer, cis-cis HOCOOH, precludes its detection. We obtain an upper limit to its abundance with respect to H2 of ≤1.2 × 10−9, which suggests that cis-cis HOCOOH might be fairly abundant in interstellar space, although it is nearly undetectable by radio astronomical observations. We derive a cis-cis/cis-trans ratio of ≤25, consistent with the smaller energy difference between both conformers compared with the relative stability of trans- and cis-formic acid. Finally, we compare the abundance of these acids in different astronomical environments, further suggesting a relationship between the chemical content found in the interstellar medium and the chemical composition of the minor bodies of the solar system, which could be inherited during the star formation process.

Theoretical Study of the Photochemical Mechanisms of the Electronic Quenching of NO(A2Σ+) with CH4, CH3OH, and CO2.

The electronic quenching of NO(A2Σ+) with molecular partners occurs through complex non-adiabatic dynamics that occurs on multiple coupled potential energy surfaces. Moreover, the propensity for NO(A2Σ+) electronic quenching depends heavily on the strength and nature of the intermolecular interactions between NO(A2Σ+) and the molecular partner. In this paper, we explore the electronic quenching mechanisms of three systems: NO(A2Σ+) + CH4, NO(A2Σ+) + CH3OH, and NO(A2Σ+) + CO2. Using EOM-EA-CCSD calculations, we rationalize the very low electronic quenching cross-section of NO(A2Σ+) + CH4 as well as the outcomes observed in previous NO + CH4 photodissociation studies. Our analysis of NO(A2Σ+) + CH3OH suggests that it will undergo facile electronic quenching mediated by reducing the intermolecular distance and significantly stretching the O-H bond of CH3OH. For NO(A2Σ+) + CO2, intermolecular attractions lead to a series of low-energy ON-OCO conformations in which the CO2 is significantly bent. For both the NO(A2Σ+) + CH3OH and NO(A2Σ+) + CO2 systems, we see evidence of the harpoon mechanism and low-energy conical intersections between NO(A2Σ+) + M and NO(X2Π) + M. Overall, this work provides the first detailed theoretical study on the NO(A2Σ+) + M potential energy surface of each of these systems and will inform future velocity map imaging experiments.

Shedding light into the biological activity of aminopterin, via molecular structural, docking, and molecular dynamics analyses

In this study, the structural and anticancer properties of aminopterin, as well as its antiviral characteristics, were elucidated. The preferred conformations of the title molecule were investigated with semiempirical AM1 method, and the obtained the lowest energy conformer was then optimized by using density functional (DFT/B3LYP) method with 6-311++G(d,p) as basis set. The vibrational frequencies of the optimized structure were calculated by the same level of theory and were compared with the experimental values. The vibrational assignments were performed based on the computed potential energy distribution (PED) of the vibrational modes. The molecular electrostatic potential (MEP) and frontier molecular orbitals (HOMO, LUMO) analyses were carried out for the optimized structure and the chemical reactivity has been scrutinized. To enlighten the biological activity of aminopterin as anticancer and anti-COVID-19 agents, aminopterin was docked into DNA, αIIBβ3 and α5β1integrins, human dihydrofolate reductase, main protease (Mpro) of SARS-CoV-2 and SARS-CoV-2/ACE2 complex receptor. The binding mechanisms of aminopterin with the receptors were clarified. The molecular docking results revealed the strong interaction of the aminopterin with DNA (−8.2 kcal/mol), αIIBβ3 and α5β1 integrins (−9.0 and −10.8 kcal/mol, respectively), human dihydrofolate reductase (−9.7 kcal/mol), Mpro of SARS-CoV-2 (−6.7 kcal/mol), and SARS-CoV-2/ACE2 complex receptor (−8.1 kcal/mol). Moreover, after molecular docking calculations, top-scoring ligand-receptor complexes of the aminopterin with SARS-CoV-2 enzymes (6M03 and 6M0J) were subjected to 50 ns all-atom MD simulations to investigate the ligand-receptor interactions in more detail, and to determine the binding free energies accurately. The predicted results indicate that the aminopterin may significantly inhibit SARS-CoV-2 infection. Thus, in this study, as both anticancer and anti-COVID-19 agents, the versatility of the biological activity of aminopterin was shown. Communicated by Ramaswamy H. Sarma

Syntheses, characterization of Imidazo[4,5-f][1,10]phenanthroline derivative and As (III) complex, In vitro evaluation, the determine of apoptosis mechanism; theoretical and quantum studies

In the present work, a novel ligand, (4-amino-3-methoxybenzaldehyde)-1H-imidazo[4,5-f][1,10] phenanthroline (AMIP) based on the formation of an imidazole ring and [As(AMIP)](Cl)]Cl2 was synthesized and characterized through Fourier-transform infrared (FT-IR) spectroscopy. In addition, the anticancer activity of [As(AMIP)](Cl)]Cl2 complex was tested against human acute promyelocytic leukemia cells (HL-60) and granulocytic differentiation of human promyelocytic leukemia cells (NB4). The MTT results showed IC50 values of 7.31 ± 15 and 8.4 ± 62 μM for As (III) complex against NB4 and HL-60, respectively. In a study on both cell lines, As (III) reduced gene expression Bcl-2 and Bcl-xl, increased Bax and Bad, and activated caspase-3, resulting in apoptosis. The dye Hoechst 33342 showed increased apoptosis induction in the NB4 cell line than in the HL-60 cell line. BrdU test exhibited an inhibitory effect on DNA synthesis. The protein levels of caspase-3 were enhanced in a dose-dependent manner in both HL-60 and NB-4 cell lines. Based on the Annexin V-FITC/PI assay, apoptosis was the primary mechanism of cell death. The real-time polymerase chain reaction (real-time PCR) results demonstrated that the expression level of Atg 12, Atg 7, Lc 3, and Beclin-1 genes, antiapoptotic genes including Bcl-2 and Bcl-xl, and apoptotic genes containing BAD and BAX was improved. Furthermore, the hemolysis assay showed the anti-hemolytic activity of the complex. Moreover, quantum chemical calculations were utilized to optimize all structures, and the output results were employed to study molecular docking of compounds with caspase-3 tethered to irreversible inhibitor (PDB ID: 1NMS) and DNA with sequence d(CCGTCGACGG) (PDB ID:423D). The results showed that As (III) complex had the lowest-energy conformation, suggesting the optimal interaction.

QMugs 1.1: Quantum mechanical properties of organic compounds commonly encountered in reactivity datasets

Here, the Quantum Mechanical Properties of Drug-like Molecules (QMugs) dataset is expanded to facilitate its use as training data for surrogate machine learning models to predict quantum mechanical properties for tasks related to chemical reactivity. Small molecules from reaction databases as well as charged and boron-containing compounds from ChEMBL were added. Each of these compounds was passed through a pipeline of MMFF94s/UFF conformer generation, followed by GFN2-xTB optimization and finally a density functional theory single-point calculation at the ωB97X-D/def2-SVP level of theory. In total, 71,632 new molecules were evaluated in this manner. Steric (SASA) and dispersion (Pint) descriptors were computed at the semiempirical GFN2-xTB level of theory for the lowest energy conformer of all species in the enlarged QMugs dataset. The expanded dataset aims to facilitate the construction of surrogate models of much broader scope than the original QMugs dataset which was limited to biologically active compounds.