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We elucidate the mechanism of the manganese-catalyzed N-alkylation of aniline with benzyl alcohol mediated by a bis(1,2,3-triazolylidene) Mn(I) complex through a combination of experimental studies and density functional theory (DFT) calculations. Activation of the precatalyst by a base leads to the formation of an anionic alkoxo complex featuring a deprotonated methylene bridge, which is identified as the catalytically active species. Notably, the methylene linker exhibits previously unrecognized noninnocent behavior, undergoing reversible deprotonation and participating directly in proton-transfer steps of the catalytic cycle. Kinetic isotope effects and deuterium-labeling experiments support the involvement of both hydride transfer and alcohol-assisted proton processes in the rate-determining steps. These findings uncover a new mode of metal-ligand cooperation in triazolylidene-based manganese catalysts and provide mechanistic guidelines for the design of cooperative ligands in base-metal-borrowing hydrogen catalysis. Show less

Water is arguably one of the most important chemicals essential for the functioning of biological molecules. In the context of DNA, it plays a crucial role in stabilizing and modulating its structure and function. The discovery of water-bound motifs in crystal structures has greatly improved our understanding of the interactions between structured water molecules and DNA. In this manuscript, we review the role of water in mediating biologically relevant DNA structures, in particular those arising from epigenetic modifications and higher-order structures such as G-quadruplexes and i-motifs. We also examine water-mediated interactions between DNA and various small molecules, including groove binders and intercalators, and emphasize their importance for DNA function and therapeutic development. Finally, we discuss recent advances in tools and techniques for predicting water interactions in nucleic acid structures. By offering a fresh perspective on the role of water, this review underscores its importance as a molecular modulator of DNA structure and function. Show less

Photocatalytic cancer therapy (PCT) has emerged as a cutting-edge anticancer mechanism of action, harnessing light energy to mediate the catalytic oxidation of intracellular substrates. PCT is of significant current importance due to its potential to address the limitations of conventional chemotherapy, particularly drug resistance and side effects. This approach offers a noninvasive, targeted cancer treatment option by utilizing metal-based photocatalysts to induce redox and metabolic disorders within cancer cells. The photocatalysts disrupt the cancer cell metabolism by converting NADH/NAD(P)H to NAD⁺/NAD(P)⁺ via catalytic photoredox processes, altering intracellular NAD⁺/NADH or NAD(P)⁺/NAD(P)H ratios, which are crucial for cellular metabolism. Ir(III), Ru(II), Re(I), and Os(II) photocatalysts demonstrated promising PCT efficacy. Despite these developments, gaps remain in the literature for translating this new anticancer mechanism into clinical trials. This Perspective critically examines the developments in this research area and provides future directions for designing efficient photocatalysts for PCT. Show less

ABSTRACTTo understand the nature of heterogeneous catalytic processes and improve their efficiency, it is necessary to conduct both experimental and theoretical studies. At the same time, there is no unified approach to obtaining the necessary data using quantum chemistry methods. In this work, problems of the existing calculational approaches are analyzed. The obtained information is used to develop the original three‐layer embedded cluster model approach, which is shown to be the most effective. The general algorithm for obtaining such models for various oxides is formulated. The sufficient accuracy of the proposed models in predicting geometric and energy characteristics, vibrational frequencies, activation barriers, and thermodynamic characteristics is verified. The specifics of calculating the thermodynamic characteristics of heterogeneous processes using the proposed cluster models is studied in detail. The developed approach is an effective tool for studying the mechanism of heterogeneous catalytic processes both by itself and in combination with experiment. Show less

DNA adducting drugs, including alkylating agents and platinum-containing drugs, are prominent in cancer chemotherapy. Their mechanisms of action involve direct interaction with DNA, resulting in the formation of DNA addition products known as DNA adducts. While these adducts are well-accepted to induce cancer cell death, understanding of their specific chemotypes and their role in drug therapy response remain limited. This perspective aims to address this gap by investigating the metabolic activation and chemical characterization of DNA adducts formed by the U.S. FDA-approved drugs. Moreover, clinical studies on DNA adducts as potential biomarkers for predicting patient responses to drug efficacy are examined. The overarching goal is to engage the interest of medicinal chemists and stimulate further research into the use of DNA adducts as biomarkers for guiding personalized cancer treatment. Show less

Targeting of G-quadruplex (G-Q) nucleic acids, which are helical four-stranded structures formed from guanine-rich nucleic acid sequences, has emerged in recent years as an appealing opportunity for drug intervention in anticancer therapy. Small-molecule drugs can stabilize quadruplex structures, promoting selective downregulation of gene expression and telomerase inhibition and also activating DNA damage responses. Thus, rational design of small molecular ligands able to selectively interact with and stabilize G-Q structures is a promising strategy for developing potent anti-cancer drugs with selective toxicity towards cancer cells over normal ones. Here, the outcomes of a thorough computational investigation of a recently synthesized monofunctional Pt^II complex (Pt1), whose selectivity for G-Q is activated by what is called adaptive binding, are reported. Quantum mechanics and molecular dynamics calculations have been employed for studying the classical key steps of the mechanism of action of Pt^II complexes, the conversion of the non-charged and non-planar Pt1 complex into a planar and charged Pt^II (Pt2) complex able to play the role of a G-Q binder and, finally, the interaction of Pt2 with G-Q. The information obtained from such an investigation allows us to rationalize the behavior of the novel Pt^II complex proposed to be activated by adaptive binding toward selective interaction with G-Q or similar molecules and can be exploited for designing ligands with more effective recognition ability toward G-quadruplex DNA. Show less

Computational modeling of inhibitors for metalloenzymes in virtual drug development campaigns has proven challenging. To overcome this limitation, a technique for predicting the binding pose of metal-binding pharmacophores (MBPs) is presented. Using a combination of density functional theory (DFT) calculations and docking using a genetic algorithm, inhibitor binding was evaluated in silico and compared with inhibitor-enzyme cocrystal structures. The predicted binding poses were found to be consistent with the cocrystal structures. The computational strategy presented represents a useful tool for predicting metalloenzyme-MBP interactions. Show less

Ligand substitution at the metal center is common in catalysis and signal transduction of metalloproteins. Understanding the effects of particular ligands, as well as the polypeptide surrounding, is critical for uncovering mechanisms of these biological processes and exploiting them in the design of bioinspired catalysts and molecular devices. A series of switchable K79G/M80X/F82C (X = Met, His, or Lys) variants of cytochrome (cyt) c was employed to directly compare the stability of differently ligated proteins and activation barriers for Met, His, and Lys replacement at the ferric heme iron. Studies of these variants and their nonswitchable counterparts K79G/M80X have revealed stability trends Met < Lys < His and Lys < His < Met for the protein Fe^III-X and Fe^II-X species, respectively. The differences in the hydrogen-bonding interactions in folded proteins and in solvation of unbound X in the unfolded proteins explain these trends. Calculations of free energy of ligand dissociation in small heme model complexes reveal that the ease of the Fe^III-X bond breaking increases in the series amine < imidazole < thioether, mirroring trends in hardness of these ligands. Experimental rate constants for X dissociation in differently ligated cyt c variants are consistent with this sequence, but the differences between Met and His dissociation rates are attenuated because the former process is limited by the heme crevice opening. Analyses of activation parameters and comparisons to those for the Lys-to-Met ligand switch in the alkaline transition suggest that ligand dissociation is entropically driven in all the variants and accompanied by Lys protonation at neutral pH. The described thiolate redox-linked switches have offered a wealth of new information about interactions of different protein-derived ligands with the heme iron in cyt c model proteins, and we anticipate that the strategy of employing these switches could benefit studies of other redox metalloproteins and model complexes. Show less

This Perspective revisits Charles Coulson's famous statement from 1959 "give us insight not numbers" in which he pointed out that accurate computations and chemical understanding often do not go hand in hand. We argue that today, accurate wave function based first-principle calculations can be performed on large molecular systems, while tools are available to interpret the results of these calculations in chemical language. This leads us to modify Coulson's statement to "give us insight and numbers". Examples from organic, inorganic, organometallic and surface chemistry as well as molecular magnetism illustrate the points made. Show less

Non-covalent interactions play an important role in chemistry, physics and especially in biodisciplines. They determine the structure of biomacromolecules such as DNA and proteins and are responsible for the molecular recognition process. Theoretical evaluation of interaction energies is difficult; however, perturbation as well as variation (supermolecular) methods are briefly described. Accurate interaction energies can be obtained by complete basis set limit calculations providing a large portion of correlation energy is covered (e.g. by performing CCSD(T) calculations). The role of H-bonding and stacking interactions in the stabilisation of DNA, oligopeptides and proteins is described, and the importance of London dispersion energy is shown. Show less