Thiopurine S-methyltransferase (TPMT) is crucial for catalyzing the inactivation and reducing the toxicity of thiopurine class of immunosuppressive drugs which are FDA-approved to treat autoimmune diseases and transplant rejection. Its complete or partial loss of activity during standard-dose thiopurine treatment causes severe bone marrow suppression and death. Therefore, FDA recommends testing TPMT activity to identify patients at high risk of developing life-threatening complications. Here, we tested whether human TPMT is vulnerable to off-target interaction with one of the most commonly prescribed antihypertensive drug telmisartan. The comprehensive molecular modeling in this study shows for the first time that active site of TPMT accommodates telmisartan in a bi-substrate-like binding mode. Consequently, this blocks the co-factor and thiopurine substrate binding subsites in the active site while preserving TPMT's secondary structure. The spatial arrangement and favorable interactions enabled by the interconnected co-factor and thiopurine substrate binding sites causes a stronger binding affinity for telmisartan compared to TPMT's natural co-factors. This study has identified a previously unrecognized mechanism of interaction between TPMT, a biomacromolecule of major importance in thiopurine drug metabolism, and telmisartan, highlighting the necessity for further studies to evaluate adverse interactions of telmisartan with TPMT when co-administered with thiopurine immunosuppressants.

Cathepsin S (CatS), a cysteine protease, catalyzes the cleavage of immunoregulatory peptides and mediates tissue destruction in autoimmune and inflammatory diseases. Plasticity of its ligand binding site and mechanisms of dynamic transitions between different conformational states are critical in drug discovery; however, knowledge of its entire conformational landscape and transition mechanisms remains incomplete. Therefore, we investigated the atomic-level interactions between active site cleft residues that contribute to its structural and functional plasticity. Here, we show that the hinge movement of side chains of Phe211, Phe70, and Tyr118, followed by side chain reorientation of active site residues and inter-residue interactions, results in open or closed conformations, contributing to the plasticity of the S2 binding affinity hotspot pocket of CatS. Hinge movements of Phe211, Phe70, and Tyr118 regulate the space available in the S2 pocket, with Phe70 acting as a key regulator, thereby affecting small molecule binding in the active site cleft. Further, the non-covalent interactions between active site residues during transitions between open and closed states lead to the formation of three distinct, dynamic, semi-closed substates. The transition to the closed state can be blocked by a ligand that sterically hinders the hinge movement of Phe70 or Phe211. The cooperative, organized side chain rotation of Phe211, Phe70, and Tyr118, and subsequent emergence of non-covalent interactions between the active site residues can influence the accommodation of ligands and their specificity. These novel findings might further aid the design of selective small molecule drugs targeting specific conformational states of the immunoregulatory and inflammatory/autoimmune disease target human CatS.

The loss of proteolytic activity of ADAM17 causes birth defects and embryonic lethality. Conversely, inhibiting ADAM17 activity represents a potential strategy for treating inflammatory and autoimmune diseases. ADAM17 has an active site cleft with a divalent Zn ion and hydrophobic S1’/S3’ subsites interconnected to form an L shaped cavity. However, it is currently unknown whether the active site of ADAM17 is susceptible to off-target inhibition by the small molecule drug eltrombopag, which contains metal-binding moieties and is classified as pregnancy category C by the FDA. The in-depth molecular modeling analysis in this study revealed that the unique structural features of L-shaped S1’/S3’, crucial for determining ADAM17 specificity, along with spatial constraints imposed by active site amino acid residues, create an ideal binding environment for eltrombopag. Interestingly, the structural peculiarity of L-shaped S1’/S3’ cavity enabled the carboxylate group rather than the traditionally recognized metal binding domain of eltrombopag to chelate catalytic Zn of ADAM17. Further, eltrombopag's biphenyl and xylene groups embed in the S1’/S3’ subsites and pyrazole and hydrazine linker occupy the interconnecting tunnel, forming a stable eltrombopag-ADAM17 complex. These novel findings from molecular modeling suggest that ADAM17 is an off-target of eltrombopag, a drug used to increase platelet production in thrombocytopenia. They stimulate further in vitro and in vivo studies to test the repurposing potential of eltrombopag as an ADAM17 inhibitor to prevent tissue destruction in autoimmune diseases in adults and whether the use of eltrombopag during pregnancy could potentially lead to developmental toxicity due to ADAM17 inhibition.

Modulation of the electronic states of a semiconductor is an intriguing area of research because of its interesting applications. In general, physical methods are used to reversibly manipulate the bandgap of semiconductors. Herein, we have used a simple molecule, ammonia, and allowed it to intercalate inside the crystal lattice of CsPbBr3 perovskites to alter the band positions. The molecular intercalation of ammonia induces strain in the crystal structure of perovskite, which widens the bandgap. Ammonia intercalation results in fall-off of the visible absorption and emission of the CsPbBr3 perovskites and a new absorption emerges in the ultraviolet region. Interestingly, with time, the deintercalation takes place, as a result of the population in the antibonding orbitals formed due to the mixing of s orbital of the Pb and p orbital of N in the intercalated NH3. The deintercalation of gaseous ammonia results in the narrowing of the bandgap which results in the regaining of the visible absorption. Together with the density functional theory calculations, herein, we demonstrate the reversible bandgap modulation in CsPbBr3 perovskite nanocrystals. Aspects discussed here can give directions to develop newer methodologies to tune the band positions of semiconductors by the intercalation of the right molecules inside their crystal lattice.

Structural degradation of all inorganic CsPbBr3 in the presence of moisture is considered as one of its major limitations to use as an active component in various light-harvesting and light-emitting devices. Herein, we used two similar molecules, H2O and H2S, with similar structures, to follow the decomposition mechanism of CsPbBr3 perovskite nanocrystals. Interestingly, H2O acts as a catalyst for the decomposition of CsPbBr3, which is in contrast to H2S. Our experimental observations followed by density functional theory (DFT) calculations showed that the water molecule is intercalated in the CsPbBr3 perovskite whereas H2S is adsorbed in the (100) planes of CsPbBr3 by a weak electrostatic interaction. According to Pearson's hard-soft acid-base theory, both cations present in CsPbBr3 prefer soft/intermediate bases. In the case of the water molecule, it lacks a soft base and thus it is not directly involved in the reaction whereas H2S can provide a soft base and thus it gets involved in the reaction. Understanding the mechanistic aspects of decomposition can give different methodologies for preventing such unwanted reactions.

Inhibition of a disintegrin and metalloproteinase-17 (ADAM17), a metzincin, is proposed as a novel therapeutic strategy to suppress overproduction of the proinflammatory cytokine TNF-α in rheumatoid arthritis and inflammatory bowel disease. Existing ADAM17 inhibitors generate toxic metabolites in-vivo or haven't progressed in clinical trials. Previous studies suggest that ligands which bind to ADAM17 active site by interacting with the Zn ion and L-shaped hydrophobic S1'- and S3'-pockets and forming favorable hydrogen bonds could act as potential ADAM17 inhibitors. Here, we investigated whether the FDA-approved anti-bacterial drug ceftolozane, a cephalosporin containing aromatic groups and carboxyl groups as probable zinc binding groups (ZBGs), forms non-covalent interactions resulting in its binding in the active site of ADAM17. In this study, the density functional theory (DFT), molecular docking and molecular dynamics calculations with the catalytic chain of ADAM17 show that carboxyl group of ceftolozane acts as moderate ZBG, and its extended geometry forms hydrogen bonds and hydrophobic interactions resulting in a binding affinity comparable to the co-crystallized known ADAM17 inhibitor. The favorable binding interactions identified here suggest the potential of ceftolozane to modulate ADAM17 activity in inflammatory diseases. ADAM17 cleaves and releases epidermal growth factor (EGF) ligands from the cell surface. The shed EGF ligands then bind to the EGF receptors to drive embryonic development. Therefore, our findings also suggest that use of ceftolozane during pregnancy may inhibit ADAM17-mediated shedding of EGF and thus increase the risk of birth defects in humans.Communicated by Ramaswamy H. Sarma.

The affinity of chloride/iodide ions to replace the lattice sites of bromide ions in the CsPbBr3 nanocrystals by anion exchange reactions is investigated. In the presence of an equal number of iodide and chloride ions, the absorption and emission of lead halide perovskites are found to be red-shifted as a result of the preferential anion exchange with the iodide ions. In order to initiate the anion exchange reactions with the chloride ions from a mixture of chloride and iodide ions, a minimum of 66 % of chloride ions, is essential to observe a significant change. The differential affinity of chloride/iodide ions to substitute bromide ions in CsPbBr3 perovskite is also substantiated using density functional theory (DFT) calculation. Understanding the interactions in the crystal structure of lead halide perovskites can give directions to tune the material properties in the nanoscale for various applications in science and technology.

Replacement of carbon atoms from aromatic molecules and their two-dimensional extended analogues (graphene) have been predicted to have interesting structural diversity and tunable electronic properties. Recent progress in the experimental realization of such systems is discussed along with a conceptual understanding of the structural properties of planar organosilicon compounds and silicene. Psuedo Jahn-Teller (PJT) distortion is shown to contribute to the buckling distortions in silicene which make them excellent materials for band-gap tuning through hydrogenation. Chemical doping of silicene by cations is suggested to be a strategy to suppress buckling of silicene and regain its perfect planar two-dimensional silicon framework. TERS spectroscopy is proposed as a tool to probe the presence or absence of buckling distortions in silicene and cation doped silicene respectively.

Recent engine design and emission trends have led to the commercial use of Atmospheric Plasma Spray (APS) coatings for cylinder liner applications like the TiO2 APS coating. It was shown in our previous work that this type of coating showed better friction results compared to steel lubricated with MoDTC. To further investigate this feature, a parametric study was carried out involving the effect of MoDTC concentration, test temperature, Hertzian contact pressure and the change of counterpart materials from steel balls to ceramic balls (Al2O3 and ZrO2). Ball-on-flat tribotests were carried out on a reciprocating (ball-on-flat) tribometer lubricated with base oil containing MoDTC. Results show that for all the test conditions used including the concentration of MoDTC, test temperature and the contact pressure, lower friction and wear is observed for the TiO2 APS coating compared to reference steel. To explain the low friction behavior, tribofilm compositions were investigated and it was observed that MoS2 is always formed in the case of TiO2 APS with no oxysulphide species. For the reference steel, MoOxSy species are mainly detected in the tribofilms. XPS analyses performed on TiO2 APS flats when the counterpart material was changed from steel balls to ceramic balls suggested the formation of MoS2 (Mo in +iv oxidation state) and Mo-C (Mo in +iv or +ii oxidation state) species with a negligible amount of MoO3 (Mo in +vi oxidation state). It was also shown that a significant amount of molybdenum atoms inside the tribofilm, originating from MoDTC (Mo in +v oxidation state) were reduced in the tribological contact. A mechanism for the decomposition of MoDTC on the basis of tribocatalytic behaviour hypothesized in our previous work was proposed and discussed.

The ground-state structures, HOMO-LUMO gaps, singlet triplet splitting, and the UV-vis absorption spectra for Si, Ge-substituted analogues of the recently synthesized disk-like pi-conjugated molecules, like octathio[8]circulene, popularly termed "sulflower", and 2H-benzo[cd]pyrene, popularly termed "olympicene", are studied using density functional theory. Unlike their pure organic counterparts, these molecules are found to be nonplanar with substantial puckering from the high symmetric structures. The origin of puckering is traced to pseudo Jahn-Teller (PJT) distortions due to favorable mixing of the occupied molecular orbitals (OMO) and unoccupied molecular orbitals (UMO). Even though the HOMO-LUMO and singlet triplet gaps for these molecules are smaller than their organic counterparts, the reorganization energies (both hole, lambda(h), and electron, lambda(e)) for the Si, Ge analogues of sulflower and olympicene are much higher. Therefore, these molecules are expected to be rather inefficient for field effect transistor (FET) device fabrication.

Most of the molecules react to form products by climbing a barrier. The energy involved in this climbing of the barrier is known as the activation energy of the reaction. Questions like how fast a reaction occurs can be answered by considering the height of the barrier. However, in some reactions, the reactants transform to products by directly tunnelling across the barrier instead of climbing over it. Such a purely quantum mechanical effect, which becomes more prominent for reactions at low temperatures can lead to interesting and even completely unexpected products. This effect and its consequences in representative examples are discussed.

(Centre) Ayan Datta is at IACS, Kolkata. His research interests span across various aspects of theoretical chemistry, structure and reactivity of clusters and molecular materials. Most of the molecules react to form products by climbing a barrier. The energy involved in this climbing of the barrier is known as the activation energy of the reaction. Questions like how fast a reaction occurs can be answered by considering the height of the barrier. However, in some reactions, the reactants transform to products by directly tunnelling across the barrier instead of climbing over it. Such a purely quantum mechanical effect, which becomes more prominent for reactions at low temperatures can lead to interesting and even completely unexpected products. This effect and its consequences in representative examples are discussed.

The discovery of graphene and its remarkable and exotic properties have aroused interest in other elements and molecules that form 2D atomic layers, such as metal chalcogenides, transition metal oxides, boron nitride, silicon, and germanium. Silicene and germanene, the Si and Ge counterparts of graphene, have interesting fundamental physical properties with potential applications in technology. For example, researchers expect that silicene will be relatively easy to incorporate within existing silicon-based electronics. In this Account, we summarize the challenges and progress in the field of silicene research. Theoretical calculations have predicted that silicene possesses graphene-like properties such as massless Dirac fermions that carry charge and the quantum spin Hall effect. Researchers are actively exploring the physical and chemical properties of silicene and tailoring it for wide variety of applications. The symmetric buckling in each of the six-membered rings of silicene differentiates it from graphene and imparts a variety of interesting properties with potential technological applications. The pseudo-Jahn-Teller (PJT) distortion breaks the symmetry and leads to the buckling in silicenes. In graphene, the two sublattice structures are equivalent, which does not allow for the opening of the band gap by an external electric field. However, in silicene where the neighboring Si atoms are displaced alternatively perpendicular to the plane, the intrinsic buckling permits a band gap opening in silicene in the presence of external electric field. Silicene's stronger spin orbit coupling than graphene has far reaching applications in spintronic devices. Because silicon prefers sp(3) hybridization over sp(2), hydrogenation is much easier in silicene. The hydrogenation of silicene to form silicane opens the band gap and increases the puckering angle. Lithiation can suppress the pseudo-Jahn-Teller distortion in silicene and hence can flatten silicene's structure while opening the band gap. So far, chemists have not successfully synthesized and characterized a free-standing silicene. But recently chemists have successfully produced silicene sheets and nanoribbons over various substrates such as silver, diboride thin films, and iridium. The supporting substrate critically controls the electronic properties of silicene, and the match of the appropriate support and its use is critical in applications of silicene.

Silicene, the all-Si analogue of graphene, is symmetrically buckled in each of the six-membered units and this buckling is periodically translated across the surface. Raman spectra of silicene clusters were calculated using first principles DFT methods to explore the intrinsic buckling in silicene. The presence of metal clusters as a tip over the silicene units affects the intensity of the buckling modes which can be enhanced by increasing the number of atoms in the clusters. The favourable sites of chemisorption of metal clusters over the silicene surface are studied along with the resulting red shift in buckling frequency and chemical enhancement in the Raman intensity.

First principles calculations based on DFT have been performed on crystals of halides (X = F, Cl, Br and I) of alkali metals (M = Li, Na, K, Rb and Cs). The calculated lattice energies (U0) are in good agreement with the experimental lattice enthalpies. A new exact formalism is proposed to determine the Born exponent (n) for ionic solids. The values of the Born exponent calculated through this ab-initio technique is in good agreement with previous empirically derived results. Band Structure calculations reveal that these compounds are wide-gap insulators that explains their optical transparency. Projected density of states (PDOS) calculations reveal that alkali halides with small cations and large anions, have small band gaps due to charge transfer from X → M. This explains the onset of covalency in ionic solids, which is popularly known as the Fajans Rule.

CH···π and lone-pair···π interactions are estimated for a series of conformationally dynamic bicyclic N-aryliimides. On the basis of their strengths and mutual synergy/competition, the molecules prefer a folded/unfolded conformation. Calculations suggest strategies to selectively isolate the folded form by increasing the strength of the attractive CH···π interaction or removing the lone-pair···π repulsion. While the barrier for the folded ⇄ unfolded transformation is too large to conformationally lock the molecules in either of the conformers, the dynamics for hopping of the alkyl group across rings and tumbling over the rings are found to be facile in the folded conformation.

Photophysical and density functional studies on a nitrobenzoxadiazole-based system, 4-(2-diphenylphosphinoethylamino)-7-nitro-2,1,3-benzoxadiazole (1), have been carried out in acetonitrile medium to determine the nature of interaction between 1 and different biologically and environmentally relevant metal ions. Quantum mechanical calculations have been carried out to find out the molecular origin of fluorophore–metal interactions. Higher fluorescence enhancement values of the system in presence of Fe(III) and Cr(III) has been attributed to the stabilization interactions between the P-atom of the receptor with M(III) as well as the π-overlapping of the aromatic rings (through the formation of η6 complexes).

Silicene, the all Si analogue of graphene is structurally different due to the presence of buckling distortions in the individual six membered rings. The sufficiently strong coupling between the unoccupied molecular orbitals (UMOs) with occupied molecular orbitals (OMOs) leads to pseudo-Jahn-Teller distortion (PJT) and the characteristic buckling in silicenes. sigma-pi separation analyses reveal that the sigma-backbone gets stabilized, whereas the pi-backbone is destabilized due to buckling. However, the stabilization of puckering sigma-backbone overwhelms the pi-backbone destabilization. This is exactly opposite to that of graphene. The cations like Li+ can suppress the PJT distortions resulting in a planar structure. This leads to opening of band gap (similar to 1.62 eV). Si substituted benzenes binds more strongly with Li+ than benzene. The mutual competition/synergy between the orbital interactions of the ring with the cation and the pi-charge density across the surface of molecule governs the stability of these complexes.

The more the better: Calculations and crystal-structure analyses show that a single electron-rich aromatic ring can simultaneously bind to two cations on its top and bottom π surfaces (see picture).

Erfolgreich getunnelt: Der schnelle und temperaturabhängige intramolekulare Protonentransfer in Thiotropolon erfolgt ausschließlich durch quantenmechanisches Tunneln (siehe Bild). In Tropolon ist die Tunnelbarriere dagegen kleiner und breiter, was zu niedrigeren Protonentransfergeschwindigkeiten bei Temperaturen unter 240 K führt. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.