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Options to improve the extrapolation power of the neural network designed using the SchNetPack package with respect to top docking scores prediction are presented. It is shown that hyperparameter tuning of the atomistic model representation (in the schnetpack.representation) improves the prediction of the top scoring compounds, which have characteristically a low incidence in randomized data sets for training of machine learning models. The prediction robustness is evaluated according to the mean square error (MSE) and the entropy of the average loss landscape decrease. Admittedly, the improvement of the top scoring compounds' prediction accuracy comes with the penalty of worsening the overall prediction power. It is revealed that the most impactful hyperparameter is the cutoff (5 Å is reported as the optimal choice). Other parameters (e.g., number of radial basis functions, number of interaction layers of the neural network, feature vector size or its batch size) are found to not affect the prediction robustness of the top scoring compounds in any comparable way relative to the cutoff. The MSE of the best docking score prediction (below -13 kcal/mol) improves from ca. 3.5 to 0.9 kcal/mol, while the prediction of less potent compounds (-13 to -11 kcal/mol) shows a lesser improvement, i.e., a decrease of MSE from 1.6 to 1.3 kcal/mol. Additionally, oversampling and undersampling of the training set with respect to the top scoring compounds' abundance is presented. The results indicate that the cutoff choice performs better than over - or undersampling of the training set, with undersampling performing better than oversampling .

Cobalt complexes with multiproton- and multielectron-responsive ligands are of interest for challenging catalytic transformations. The chemical and redox noninnocence of pentane-2,4-dione bis( S -methylisothiosemicarbazone) (PBIT) in a series of cobalt complexes has been studied by a range of methods, including spectroscopy [UV-vis, NMR, electron paramagnetic resonance (EPR), X-ray absorption spectroscopy (XAS)], cyclic voltammetry, X-ray diffraction, and density functional theory (DFT) calculations. Two complexes [Co III (H 2 L SMe )I]I and [Co III ( L SMe )I 2 ] were found to act as precatalysts in a Wacker-type oxidation of olefins using phenylsilane, the role of which was elucidated through isotopic labeling. Insights into the mechanism of the catalytic transformation as well as the substrate scope of this selective reaction are described, and the essential role of phenylsilane and the noninnocence of PBIT are disclosed. Among the several relevant species characterized was an unprecedented Co(III) complex with a dianionic diradical PBIT ligand ([Co III (L SMe•• )I])., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Herein, we present the capacity of three different molecular docking programs (AutoDock, AutoDock Vina, and PLANTS) to identify and reproduce the binding modes of ligands present in 247 covalent and 169 noncovalent complex crystal structures of the severe acute respiratory syndrome coronavirus 2 main protease (M pro ). The compromise in docking power is evaluated with respect to their ability to generate poses similar to the crystal structure binding mode (heavy atoms' root-mean-square deviation < 2 Å) and their ability to recognize the native binding mode with an included compensation for the scoring function error. Noncovalently bound inhibitors are best modeled by AutoDock Vina (90.6% success rate in the active site), while the most relevant results for covalently bound inhibitors are produced by PLANTS (93.0%). AutoDock shows acceptable performance for both types of ligands, 81.1 and 76.4% for noncovalent and covalent complexes, respectively. All three programs manifest worse performance when reproducing surface-bound ligands. Comparison with other works illustrates the importance of crystal structure processing (12% of noncovalent and 26% of covalent ligands had to be manually corrected), proper sampling protocol settings, and inclusion of root-mean-square deviation (RMSD)/scoring function error compensations in crystal structure pose identification. Results are analyzed with respect to a clustering scheme of the noncovalently bound ligands and the chemical reaction type of the covalent ligand bound to the Cys145 residue. A comparison of screening power based on the docking scores of noncovalent ligands from the crystal structures with a "Directory of Useful Decoys, Enhanced" set of known decoys (6562 compounds) and ZINC15 in vivo subset (60,394 compounds) is provided. Ligand and protein input files are provided for future benchmarking purposes.

The anti ( a ) to syn ( s ) isomerization pathway of the deprotonated form of the dimer with two nickel(II) 15-membered octaazamacrocyclic units connected via a carbon-carbon (C-C) σ bond was investigated. For the initial anti ( a ) structure, a deprotonation of one of the bridging ( sp 3 hybridized) carbon atoms is suggested to allow for an a to s geometry twist. A 360° scan around the bridging C-C dihedral angle was performed first to find an intermediate geometry. Subsequently, the isomerization pathway was explored via individual steps using a series of mode redundant geometry optimizations (internal coordinates potential energy surface scans) and geometry relaxations leading to the s structure. The prominent geometries (intermediates) of the isomerization pathway are chosen and compared to the a and s structures, and geometry relaxations of the protonated forms of selected intermediates are considered., Supplementary Information: The online version contains supplementary material available at 10.1007/s00214-024-03100-5., Competing Interests: Conflict of interestsThe authors declare that they have no conflict of interest., (© The Author(s) 2024.)

Molecular docking results of two training sets containing 866 and 8,696 compounds were used to train three different machine learning (ML) approaches. Neural network approaches according to Keras and TensorFlow libraries and the gradient boosted decision trees approach of XGBoost were used with DScribe's Smooth Overlap of Atomic Positions molecular descriptors. In addition, neural networks using the SchNetPack library and descriptors were used. The ML performance was tested on three different sets, including compounds for future organic synthesis. The final evaluation of the ML predicted docking scores was based on the ZINC in vivo set, from which 1,200 compounds were randomly selected with respect to their size. The results obtained showed a consistent ML prediction capability of docking scores, and even though compounds with more than 60 atoms were found slightly overestimated they remain valid for a subsequent evaluation of their drug repurposing suitability., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The structure of 4-methyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]thiazole-2(3H)-thione (MTTOTHP) was investigated using X-ray diffraction and computational chemistry methods for determining properties of the nitrogen-oxygen bond, which is the least stable entity upon photochemical excitation. Experimentally measured structure factors have been used to determine and characterize charge density via the multipole model (MM) and the maximum entropy method (MEM). Theoretical investigation of the electron density and the electronic structure has been performed in the finite basis set density functional theory (DFT) framework. Quantum Theory of Atoms In Molecules (QTAIM), deformation densities and Laplacians maps have been used to compare theoretical and experimental results. MM experimental results and predictions from theory differ with respect to the sign and/or magnitude of the Laplacian at the N-O bond critical point (BCP), depending on the treatment of n values of the MM radial functions. Such Laplacian differences in the N-O bond case are discussed with respect to a lack of flexibility in the MM radial functions also reported by Rykounov et al. [Acta Cryst. (2011), B67, 425-436]. BCP Hessian eigenvalues show qualitatively matching results between MM and DFT. In addition, the theoretical analysis used domain-averaged fermi holes (DAFH), natural bond orbital (NBO) analysis and localized (LOC) orbitals to characterize the N-O bond as a single σ bond with marginal π character. Hirshfeld atom refinement (HAR) has been employed to compare to the MM refinement results and/or neutron dataset C-H bond lengths and to crystal or single molecule geometry optimizations, including considerations of anisotropy of H atoms. Our findings help to understand properties of molecules like MTTOTHP as progenitors of free oxygen radicals.

Three dimanganese(iii) complexes have been synthesised and fully characterised by standard spectroscopic methods and spectroelectrochemistry. Each MnIII ion is chelated by a salen type ligand (H2L), but there is variation in the bridging group: LMn(OOCCH[double bond, length as m-dash]CHCOO)MnL, LMn(OOCC6H4COO)MnL, and LMn(OOCC6H4C6H4COO)MnL. X-ray diffraction revealed an axial compression of each six-coordinate high-spin d4 MnIII ion, which is a Jahn-Teller-active ion. Temperature dependent magnetic susceptibility and variable temperature-variable field (VTVH) magnetisation measurements, as well as high-frequency and -field EPR (HFEPR) spectroscopy were used to accurately describe the magnetic properties of the complexes, not only the single-ion spin Hamiltonian parameters: g-values and zero-field splitting (ZFS) parameters D and E, but also the exchange interaction constant J between the two ions, which has been seldom determined for a di-MnIII complex, particularly when there is more than a single bridging atom. Quantum chemical calculations reproduced well the electronic and geometric structure of these unusual complexes, and, in particular, their electronic absorption spectra along with the spin Hamiltonian and exchange parameters.

Chromium species are the active sites in a variety of heterogeneous catalysts, such as the Phillips catalyst, which is composed of Cr ions supported by SiO 2 and is used to produce polyethylene. Among the catalytically relevant oxidation states of chromium is Cr IV . Families of neutral, homoleptic, four-coordinate complexes, CrL 4 , with a variety of monoanionic, monodentate ligands, such as L = alkyls, aryls, amides, ketimides (R 2 C = N - ), alkoxides, and siloxides, are available and can provide information regarding Cr sites in heterogeneous materials. For example, the previously reported siloxide, Cr(DTBMS) 4 , where DTBMS = - OSiMe t Bu 2 (di- tert-butylmethylsiloxide), may be considered a molecular analogue of Cr IV supported by SiO 2 . Such CrL 4 complexes can have either a singlet ( S = 0) or triplet ( S = 1) spin ground state, and the spin state preferences of such complexes are not fully understood. A truly tetrahedral d 2 S = 1 complex would exhibit no zero-field splitting (zfs), and the zfs is indeed small and observable by X-band EPR for several CrR 4 and Cr(OR) 4 complexes. In contrast, Cr(DTBMS) 4 has zfs beyond the range amenable to X-band EPR so that high-frequency and high-field EPR (HFEPR) is appropriate. HFEPR of Cr(DTBMS) 4 in the solid state shows the presence of three very similar triplet species with the major component having D = +0.556 cm -1 . Classical ligand-field theory (LFT) and quantum chemical theory (QCT), including ab initio methods, use EPR and electronic absorption spectra to give a complete picture of the electronic structure of Cr(DTBMS) 4 , and other complexes of formula Cr(ER n ) 4 , E = C, n = 3; E = N, n = 2; E = O, n = 1; E = F, n = 0. Computations show the importance of ligand steric bulk and of π-bonding in controlling the subtleties of electronic structure of CrL 4 species. These electronic structure results, including zfs, which is a measure of excited state accessibility, for both triplet and singlet excited states, might be related to the catalytic activity of paramagnetic Cr species.

A series of Mn(II) complexes of differently substituted pyridinophane ligands, (Py 2 NR 2 )MnCl 2 (R = i Pr, Cy) and [(Py 2 NR 2 )MnF 2 ](PF 6 ) (R = i Pr, Cy, t Bu) are synthesized and characterized. The electrochemical properties of these complexes are investigated by cyclic voltammetry, along with those of previously reported (Py 2 NMe 2 )MnCl 2 and the Mn(III) complex [(Py 2 NMe 2 )MnF 2 ](PF 6 ). The electronic structure of this and other Mn(III) complexes is probed experimentally and theoretically, via high-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy ab initio quantum chemical theory (QCT), respectively. These studies show that the complexes contain relatively typical six-coordinate Mn(III). The catalytic activity of these complexes toward both H 2 O 2 disproportionation and H 2 O oxidation has also been investigated. The rate of H 2 O 2 disproportionation decreases with increasing substituent size. Some of these complexes are active for electrocatalytic H 2 O oxidation; however this activity cannot be rationalized in terms of simple electronic or steric effects.

A new high-spin d 4 roughly trigonal-bipyramidal (TBP) manganese(iii) complex with a salen type ligand (H 2 L), namely MnL(NCS)·0.4H 2 O, has been synthesised and characterised by elemental analysis, ESI mass spectrometry, IR and UV-vis spectroscopy, and spectroelectrochemistry. X-ray diffraction analysis revealed an axial compression of the approximate TBP. Temperature dependent magnetic susceptibility and variable-temperature variable-field (VTVH) magnetisation measurements, as well as high-frequency and -field EPR (HFEPR) spectroscopy, were used to accurately describe the magnetic properties of this complex and, in particular, determine the spin Hamiltonian parameters: g-values and the zero-field splitting (ZFS) parameters D and E. The HFEPR spectra allowed the extraction of fourth order ZFS parameters. Quantum chemical calculations reproduced well the electronic and geometric structures of this unusual complex and, in particular, its electronic absorption spectrum along with the spin Hamiltonian parameters.

The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar metal complexes, in particular, for platinum(ii), e.g., cis- and trans-[PtCl 2 (NH 3 ) 2 ], and a number of related compounds, of which, however, only cis-counterparts are in clinical use today. For octahedral metal complexes, this effect of geometrical isomerism on anticancer activity has not been investigated systematically, mainly because the relevant isomers are still unavailable. An example of such an octahedral complex is trans-[RuCl 4 (Hind) 2 ] - , which is in clinical trials now as its indazolium (KP1019) or sodium salt (NKP1339), but the corresponding cis-isomers remain inaccessible. We report the synthesis of Na[cis-Os III Cl 4 (κN2-1H-ind) 2 ]·(Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H 2 ind)[Os IV Cl 5 (κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[Os IV Cl 4 (κN2-1H-ind) 2 ] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1H-indazole tautomer. Fully reversible spectroelectrochemical reduction of [1] in acetonitrile at 0.46 V vs. NHE is accompanied by a change in electronic absorption bands indicating the formation of cis-[Os III Cl 4 (κN2-1H-ind) 2 ] - ([1] - ). Chemical reduction of [1] in methanol with NaBH 4 followed by addition of nBu 4 NCl afforded the osmium(iii) complex nBu 4 N[cis-Os III Cl 4 (κN2-1H-ind) 2 ] (nBu 4 N[1]). A metathesis reaction of nBu 4 N[1] with an ion exchange resin led to the isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1]·Me 2 CO was determined and compared with that of trans-[Os IV Cl 4 (κN2-1H-ind) 2 ]·2Me 2 SO (2·2Me 2 SO), also prepared in this work. EPR spectroscopy was performed on the Os III complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans-[Os IV Cl 4 (κN1-2H-ind) 2 ] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 μM in different cancer cell lines (HT29, H446, 4T1 and HEK293). HT-29 cells are less sensitive to cisplatin than 4T1 cells, but more sensitive to [1] and Na[1], as shown by decreased proliferation and viability as well as an increased late apoptotic/necrotic cell population.

High-oxidation-state metal complexes with multiply bonded ligands are of great interest for both their reactivity as well as their fundamental bonding properties. This paper reports a combined spectroscopic and theoretical investigation into the effect of the apical multiply bonded ligand on the spin-state preferences of threefold symmetric iron(IV) complexes with tris(carbene) donor ligands. Specifically, singlet (S = 0) nitrido [{PhB(Im R ) 3 }FeN], R = t Bu (1), Mes (mesityl, 2) and the related triplet (S = 1) imido complexes, [{PhB(Im R ) 3 }Fe(NR')] + , R = Mes, R' = 1-adamantyl (3), t Bu (4), were investigated by electronic absorption and Mössbauer effect spectroscopies. For comparison, two other Fe(IV) nitrido complexes, [(TIMEN Ar )FeN] + (TIMEN Ar = tris[2-(3-aryl-imidazol-2-ylidene)ethyl]amine; Ar = Xyl (xylyl), Mes), were investigated by 57 Fe Mössbauer spectroscopy, including applied-field measurements. The paramagnetic imido complexes 3 and 4 were also studied by magnetic susceptibility measurements (for 3) and paramagnetic resonance spectroscopy: high-frequency and -field electron paramagnetic resonance (for 3 and 4) and frequency-domain Fourier-transform (FD-FT) terahertz electron paramagnetic resonance (for 3), which reveal their zero-field splitting parameters. Experimentally correlated theoretical studies comprising ligand-field theory and quantum chemical theory, the latter including both density functional theory and ab initio methods, reveal the key role played by the Fe 3d z 2 (a 1 ) orbital in these systems: the nature of its interaction with the nitrido or imido ligand dictates the spin-state preference of the complex. The ability to tune the spin state through the energy and nature of a single orbital has general relevance to the factors controlling spin states in complexes with applicability as single molecule devices.

Nonheme iron enzymes perform diverse and important functions in biochemistry. The active form of these enzymes comprises the ferryl, oxidoiron(IV), [FeO](2+) unit. In enzymes, this unit is in the high-spin, quintet, S = 2, ground state, while many synthetic model compounds exist in the spin triplet, S = 1, ground state. Recently, however, Que and co-workers reported an oxidoiron(IV) complex with a quintet ground state, [FeO(TMG3tren)](OTf)2, where TMG3tren = 1,1,1-tris{2-[N2-(1,1,3,3-tetramethylguanidino)]ethyl}amine and OTf = CF3SO3(-). The trigonal geometry imposed by this ligand, as opposed to the tetragonal geometry of earlier model complexes, favors the high-spin ground state. Although [FeO(TMG3tren)](2+) has been earlier probed by magnetic circular dichroism (MCD) and Mössbauer spectroscopies, the technique of high-frequency and -field electron paramagnetic resonance (HFEPR) is superior for describing the electronic structure of the iron(IV) center because of its ability to establish directly the spin-Hamiltonian parameters of high-spin metal centers with high precision. Herein we describe HFEPR studies on [FeO(TMG3tren)](OTf)2 generated in situ and confirm the S = 2 ground state with the following parameters: D = +4.940(5) cm(-1), E = 0.000(5), B4(0) = -14(1) × 10(-4) cm(-1), g⊥ = 2.006(2), and g∥ = 2.03(2). Extraction of a fourth-order spin-Hamiltonian parameter is unusual for HFEPR and impossible by other techniques. These experimental results are combined with state-of-the-art computational studies along with previous structural and spectroscopic results to provide a complete picture of the electronic structure of this biomimetic complex. Specifically, the calculations reproduce well the spin-Hamiltonian parameters of the complex, provide a satisfying geometrical picture of the S = 2 oxidoiron(IV) moiety, and demonstrate that the TMG3tren is an "innocent" ligand.

Mononuclear nickel(II), copper(II), and manganese(III) complexes with a noninnocent tetradentate Schiff base ligand containing a disiloxane unit were prepared in situ by reaction of 3,5-di-tert-butyl-2-hydroxybenzaldehyde with 1,3-bis(3-aminopropyl)tetramethyldisiloxane followed by addition of the appropriate metal(II) salt. The ligand H2L resulting from these reactions is a 2:1 condensation product of 3,5-di-tert-butyl-2-hydroxybenzaldehyde with 1,3-bis(3-aminopropyl)tetramethyldisiloxane. The resulting metal complexes, NiL·0.5CH2Cl2, CuL·1.5H2O, and MnL(OAc)·0.15H2O, were characterized by elemental analysis, spectroscopic methods (IR, UV-vis, X-band EPR, HFEPR, (1)H NMR), ESI mass spectrometry, and single crystal X-ray diffraction. Taking into account the well-known strong stabilizing effects of tert-butyl groups in positions 3 and 5 of the aromatic ring on phenoxyl radicals, we studied the one-electron and two-electron oxidation of the compounds using both experimental (chiefly spectroelectrochemistry) and computational (DFT) techniques. The calculated spin-density distribution and localized orbitals analysis revealed the oxidation locus and the effect of the electrochemical electron transfer on the molecular structure of the complexes, while time-dependent DFT calculations helped to explain the absorption spectra of the electrochemically generated species. Hyperfine coupling constants, g-tensors, and zero-field splitting parameters have been calculated at the DFT level of theory. Finally, the CASSCF approach has been employed to theoretically explore the zero-field splitting of the S = 2 MnL(OAc) complex for comparison purposes with the DFT and experimental HFEPR results. It is found that the D parameter sign strongly depends on the metal coordination geometry.