Our Own N-layered Integrated Molecular Orbital And Molecular Mechanics Research Articles

Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

Inhibitory potential of furanocoumarins against cyclin dependent kinase 4 using integrated docking, molecular dynamics and ONIOM methods

Cyclin Dependent Kinase 4 (CDK4) is vital in the process of cell-cycle and serves as a G1 phase checkpoint in cell division. Selective antagonists of CDK4 which are in use as clinical chemotherapeutics cause various side-effects in patients. Furanocoumarins induce anti-cancerous effects in a range of human tumours. Therefore, targeting these compounds against CDK4 is anticipated to enhance therapeutic effectiveness. This work intended to explore the CDK4 inhibitory potential of 50 furanocoumarin molecules, using a comprehensive approach that integrates the processes of docking, drug-likeness, pharmacokinetic analysis, molecular dynamics simulations and ONIOM (Our own N-layered Integrated molecular Orbital and Molecular mechanics) methods. The top five best docked compounds obtained from docking studies were screened for subsequent analysis. The molecules displayed good pharmacokinetic properties and no toxicity. Epoxybergamottin, dihydroxybergamottin and notopterol were found to inhabit the ATP-binding zone of CDK4 with substantial stability and negative binding free energy forming hydrogen bonds with key catalytic residues of the protein. Notopterol exhibiting the highest binding energy was subjected to ONIOM calculations wherein the hydrogen bonding interactions were retained with significant negative interaction energy. Hence, through these series of computerised methods, notopterol was screened as a potent CDK4 inhibitor and can act as a starting point in successive processes of drug design. Communicated by Ramaswamy H. Sarma

Adaptive-Partitioning Multilayer Dynamics Simulations: 2. Implementations of the Permuted and Interpolated Adaptive-Partitioning Gradients.

Recently, an adaptive-partitioning multilayer Q1/Q2/MM method was proposed, where Q1 and Q2 denote, respectively, two distinct quantum-mechanical levels of theory and MM, the molecular-mechanical force fields. Such a multilayer model resembles the ONIOM (our own N-layered integrated molecular orbital and molecular mechanics) model by Morokuma and co-workers, but it is distinguished by on-the-fly reclassifying atoms to be Q1, Q2, or MM in dynamics simulations. To smoothly blend the levels of descriptions of the atoms, buffer zones are introduced between adjacent layers, and the energy is smoothly interpolated. In particular, the Q1/Q2 interaction energy was expressed in two different formalisms: permuted and interpolated adaptive-partitioning (PAP and IAP), respectively. While the PAP energy is based on a weighted many-body expansion, the IAP energy is derived via alchemical quantum calculations with interpolated Fock and overlap matrices. In this article, we examine in-depth the irregularities in the IAP energy near the boundary between the buffer and Q2 zones, which were found prominent in some calculations. These irregularities are due to basis-set linear dependencies, which can be effectively suppressed using a cutoff for the weighted atomic orbital coefficients. Furthermore, we derived and implemented the gradients for both PAP and IAP. Test calculations on a series of water cluster models show perfectly smooth gradients in PAP, while a minor discontinuity occurs in IAP gradients at the buffer/Q2 boundary. The energy and gradient discontinuities in IAP become smaller when moving the buffer/Q2 boundary further away from the Q1 center and when increasing the size of the basis sets used. Overall, those discontinuities are controllable, and possible ways to further diminish them are discussed.

Dispersion-corrected DFT calculations and umbrella sampling simulations to investigate stability of Chrysin-cyclodextrin inclusion complexes

The study of inclusion complexes of Chrysin (ChR) with three forms of cyclodextrins (CDs) α-, β-, and γ-CD was accomplished to examine the stability of ChR inside the central cavities of CDs. The aim of study was to identify the most suitable form of CD to improve the hydro-solubility of poorly soluble ChR bioactive molecule. Microsecond timescale molecular dynamics (MD) simulations were performed on four inclusion complexes (α-CD/ChR, β-CD/ChR, and two conformations of γ-CD/ChR) to examine the dynamics of ChR inside the cavity of CDs. The first conformation of γ-CD/ChR inclusion complex (γ-CD1/ChR) was identified to possess the highest affinity between host and guest molecule on the basis of binding energy calculated by employing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. To further strengthen the claims of classical and biased MD studies, Our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) (wB97XD/6–311+g(d,p):pm7) calculations were performed on the selected inclusion complexes. The ONIOM based complexation energy reaffirmed that ChR had highest affinity for the γ-CD1 host molecule. Further, the non-covalent interaction analysis was conducted using Multiwfn software on QM-optimized inclusion complexes with wB97XD/6–311+G(d,p) model chemistry, revealing non-covalent interactions between ChR and CDs. This atomic level information helped us to gain better insights into critical atoms of ChR and CD that participated in intermolecular interactions and identify γ-CD as a suitable host molecule for improving the hydro-solubulity of ChR. The structural insights would help to derive new derivatives of γ-CD with better host capacity.

Computational and experimental examinations of new antitumor palladium(II) complex: CT-DNA-/BSA-binding, in-silico prediction, DFT perspective, docking, molecular dynamics simulation and ONIOM

Since the design of metal complexes with better biological activities is important, herein a new palladium(II) complex bearing en and acac (en and acac stand for ethylenediamine and acetylacetonato, respectively) as its ligands, [Pd(en)(acac)]NO3 complex, was synthesized and fully characterized. Quantum chemical computations of the palladium(II) complex were done via DFT/B3LYP method. Cytotoxicity activity of the new compound on leukemia cell line (K562) was assessed via MTT method. The findings indicated that the metal complex has remarkable cytotoxic effect than cisplatin. OSIRIS DataWarrior software was employed to calculate in-silico physicochemical and toxicity parameters of the synthesized complex which rendered significant results. To comprehend the interaction type of new metal compound with macromolecules, the in depth investigation of interaction of mentioned complex with CT-DNA and BSA was accomplished by fluorescence, UV-Visible absorption spectroscopy, viscosity measurement, gel electrophoresis, FRET analysis and circular dichroism (CD) spectroscopy. On the other hand, computational molecular docking was carried out and the obtained data demonstrated that H-bond and van der Waals forces are the dominant forces for the binding of the compound to the mentioned biomolecules. Molecular dynamics simulation was also done and confirmed the stability of best docked pose of palladium(II) complex inside DNA or BSA over the time and in presence of water solvent. Also, Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) methodology based on the hybridization of quantum mechanics and molecular mechanics (QM/MM) methodology was accomplished to inquire about binding of Pd(II) complex with DNA or BSA. Communicated by Ramaswamy H. Sarma

Binding profile of a mixed-ligand silver(I) complex with DNA and Topoisomerase I

A new mixed-ligand Ag(I) complex, [Ag(daf)(phen)]NO3 (daf = 4,5-diazafluoren-9-one and dian = N-(4,5-diazafluoren-9-ylidene)aniline), was synthesized. The elemental analysis, FTIR, 1HNMR, UV–Vis spectroscopy, cyclic voltammetry, and DFT (Density Functional Theory) geometry optimization method were applied in order to predict the Ag(I) complex structure which concluded to a distorted tetrahedral N4 coordination around the Ag(I) center. A detailed in silico analysis of the bioaffinity of the complex to DNA and human DNA-Topoisomerase I was conducted using molecular docking simulations and ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) techniques. In this overall scenario, the results suggest the dominance of π-π stacking interactions of the heteroaromatic ligands in the intercalating pocket of DNA and the active site of the enzyme and the rational correlation between being a good intercalator and a potent Topoisomerase I inhibitor. In vitro DNA-binding experiments by spectrophotometric, spectrofluorometric, Voltammetric, and viscometric techniques at physiological pH also confirmed the computational results. The complex inhibited MCF-7 cell growth in a dose-dependent manner while being nontoxic on HUVEC normal cells.

Growing Spicy ONIOMs: Extending and generalizing concepts of ONIOM and many body expansions

AbstractThe ONIOM method and many extensions to it provide capabilities to treat challenging multiscale problems in catalysis and material science. Our open‐source program Spicy is a flexible toolkit for ONIOM and fragment methods. Spicy includes a generalization of multicenter‐ONIOM, a higher‐order multipole embedding scheme, and fragment methods as useful extensions of our own n‐layered integrated molecular orbital and molecular mechanics (ONIOM), which allow applying ONIOM and high accuracy calculations to a wider range of systems. A calculation on the metallo‐protein hemoglobin demonstrates the versatility of the implementation.This article is categorized under: Electronic Structure Theory > Combined QM/MM Methods Molecular and Statistical Mechanics > Molecular Interactions Quantum Computing > Theory Development

A comprehensive theoretical investigation on the thiophene hydrodesulphurisation mechanism over sulphided Co–Mo catalysts supported by ZSM-5, FAU, Beta and MCM-22 zeolites

ABSTRACT We have theoretically studied the hydrodesulphurisation (HDS) mechanism of thiophene and its hydrogenated derivatives over sulphided Co–Mo catalysts supported by four zeolites (ZSM-5, FAU, Beta, MCM-22) by a two-layer ONIOM (our Own N-layered Integrated molecular Orbital and molecular Mechanics) method. Due to low energy barriers, the thiophene can be hydrogenated to 2,3-dihydrothiophene (2,3-DHT), 2,5-dihydrothiophene (2,5-DHT) and tetrahydrothiophene (THT). Direct desulphurisation (DDS) and hydrogenolysis desulphurisation (HYD) pathways were investigated in detail. The calculated results show that in DDS mechanism of thiophene, the rate-determining step is the C–S bond cleavage. In HYD mechanisms of 2,5-DHT, 2,3-DHT and THT, the rate-determining step is hydrogen transfer on ZSM-5, FAU and Beta zeolites except MCM-22 zeolite. The HYD of 2,3-DHT and THT should occur by the stepwise pathway. But for the 2,5-DHT, the concerted pathway is probably more favourable than the stepwise pathway. The reduced density gradient (RDG), differential charge density (DCD), and local orbital locator (LOL) maps show that for all transition states (TSs), there are complicated van der Waals (VDW) and electrostatic interactions between the organic fragment and the catalytic centre.

A multiscale ONIOM study of the buckminsterfullerene (C60) Diels–Alder reaction: from model design to reaction path analysis

The hybrid ONIOM(Ourown N-layered Integrated molecular Orbital and molecular Mechanics) formalism is employed to investigate the Diels-Alder reaction of the buckminsterfullerene C60. Our computations suggest that the ONIOM2(M06-2X/6-31G(d): SVWN/STO-3G) model, enclosing both the diene and the pyracyclene fragment of C60 in the higher-layer, provides a reasonable trade-off between accuracy and computational cost as it comes to predicting reaction energetics. Moreover, the frontier molecular orbital (FMO) theory and activation strain model (ASM) are jointly relied on to rationalize the effect of -OH and -CN substituents on the activation barrier of this reaction. Finally, reaction paths are scrutinized to get insight into the various forces underpinning the process of cycloadduct formation.

A theoretical investigation on the hydrodesulphurisation mechanism of hydrogenated thiophene over Cu–Mo-modified FAU zeolite

ABSTRACT We have theoretically investigated the hydrodesulphurisation (HDS) mechanism of hydrogenated thiophene over Cu–Mo-modified FAU zeolite using a two-layer ONIOM (our Own N-layered Integrated molecular Orbital and molecular Mechanics) study. The thiophene is hydrogenated to 2,3-dihydrothiophene (2,3-DHT), 2,5-dihydrothiophene (2,5-DHT) and tetrahydrothiophene (THT) due to moderate free energy barriers. Hydrogenolysis desulphurisation (HYD) and concerted direct desulphurisation (DDS) are discussed. Ring-opening, hydrogen transfer and C−S bond cleavage steps of thiophene derivatives are involved in the HYD process. The rate-determining steps are the hydrogen transfer step for 2,5-DHT and C−S bond cracking step for 2,3-DHT and THT. The concerted DDS pathway is probably more favourable than the HYD pathway in the desulphurisation of 2,5-DHT. The difference charge density (DCD) analysis reveals that for the ring-opening process, the electrons are migrated from the organic chain to the Cu–Mo catalytic centre. The reduced density gradient (RDG) plots indicate that both steric hindrance and a weak van der Waals (VDW) interaction exist between organic fragment and catalytic centre for all transition states (TSs). The localised orbital locator (LOL) maps suggest that there are strong covalent interactions and weak VDW interactions between the atoms in the forming chemical bonds.

Theoretical Study of the Mechanism of Ribosomal Peptide Bond Formation Using the ONIOM Method.

Peptide bond formation in living cells occurs at the peptidyl transferase center (PTC) of the large ribosomal subunit and involves the transfer of the peptidyl group from peptidyl-tRNA to aminoacyl-tRNA. Despite numerous kinetic and theoretical studies, many details of this reaction -such as whether it proceeds via a stepwise or concerted mechanism- remain unclear. In this study, we calculated the geometry and energy of the transition states and intermediates in peptide bond formation in the PTC environment using the ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) method. The calculations indicated that the energy of the transition states of stepwise mechanisms are lower than those of concerted mechanisms and suggested that the reaction involves a neutral tetrahedral intermediate that is stabilized through the hydrogen-bonding network in the PTC environment. The results will lead to a better understanding of the mechanism of peptidyl transfer reaction, and resolve fundamental questions of the steps and molecular intermediates involved in peptide bond formation in the ribosome.

Simulation of Heat Flow Curves of NC‐Based Propellants – Part 1: Determination of Reaction Enthalpies and Other Characteristics of the Reactions of NC and Stabilizer DPA Using Quantum Mechanical Methods

AbstractThe heat flow curves of nitrocellulose (NC)‐based propellants are now an important assessment quantity for their quality and safety in storage and service. The measurable heat flow is the summarized effect of the rates of all the reaction heats of the reactions going on in the material. To get a detailed assessment instead the only global one requires knowing the heat flow parts caused by NC and by stabilizer reactions. For this, in turn, one needs to find the reaction enthalpies of the essential NC decomposition reactions and the stabilizer reactions at the temperature of the measurement of the heat flow. These data are not available in the literature. To get meaningful data it was necessary to use quantum mechanical calculations, here so‐called DFT (density functional theory) methods, to screen the possible reactions by transition states and the energetic situation between educts and products. For the calculation of the reaction enthalpies and the transition states, the reactants were embedded in a polarizable continuum, which simulates the NC environment for the reactants in NC and for the stabilizer reactions. In addition, to calculate bond dissociation enthalpies of NC and of nitroglycerine a type of shell model was used called ONIOM (‘Our own N‐layered Integrated molecular Orbital and molecular Mechanics’ model). The results from the determinations of reaction enthalpies are used in the second part of the publication.

Multiscale Quantum Refinement Approaches for Metalloproteins.

Biomolecules with metal ion(s) (e.g., metalloproteins) play many important biological roles. However, accurate structural determination of metalloproteins, particularly those containing transition metal ion(s), is challenging due to their complicated electronic structure, complex bonding of metal ions, and high number of conformations in biomolecules. Quantum refinement, which was proposed to combine crystallographic data with computational chemistry methods by several groups, can improve the local structures of some proteins. In this study, a quantum refinement method combining several multiscale computational schemes with experimental (X-ray diffraction) information was developed for metalloproteins. Various quantum refinement approaches using different ONIOM (our own N-layered integrated molecular orbital and molecular mechanics) combinations of quantum mechanics (QM), semiempirical (SE), and molecular mechanics (MM) methods were conducted to assess the performance and reliability on the refined local structure in two metalloproteins. The structures for two (Cu- or Zn-containing) metalloproteins were refined by combining two-layer ONIOM2(QM1/QM2) and ONIOM2(QM/MM) and three-layer ONIOM3(QM1/QM2/MM) schemes with experimental data. The accuracy of the quantum-refined metal binding sites was also examined and compared in these multiscale quantum refinement calculations. ONIOM3(QM/SE/MM) schemes were found to give good results with lower computational costs and were proposed to be a good choice for the multiscale computational scheme for quantum refinement calculations of metal binding site(s) in metalloproteins with high efficiency. Additionally, a two-center ONIOM approach was employed to speed up the quantum refinement calculations for the Zn metalloprotein with two remote active sites/ligands. Moreover, a recent quantum-embedding wavefunction-in-density functional theory (WF-in-DFT) method was also adopted as the high-level method in unprecedented ONIOM2(CCSD-in-B3LYP/MM) and ONIOM3(CCSD-in-B3LYP/SE/MM) calculations, which can be regarded as novel pseudo-three- and pseudo-four-layer ONIOM methods, respectively, to refine the key Zn binding site at the coupled-cluster singles and doubles (CCSD) level. These refined results indicate that multiscale quantum refinement schemes can be used to improve the structural accuracy obtained for local metal binding site(s) in metalloproteins with high efficiency.

Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment

Researchers have identified the β-amyloid precursor protein cleaving enzyme 1 (BACE1) in the multifactorial pathway of Alzheimer's disease (AD) as a drug target. The design and development of molecules to inhibit BACE1 as a potential cure for AD thus remained significant. Herein, we simulated two potent BACE1 inhibitors (AM-6494 and CNP-520) to understand their binding affinity at the atomistic level. AM-6494 is a newly reported potent BACE1 inhibitor with an IC50 value of 0.4 nM in vivo and now picked for preclinical considerations. Umibecestat (CNP-520), which was discontinued at human trials lately, was considered to enable a reasonable evaluation of our results. Using density functional theory (DFT) and Our Own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM), we achieved the aim of this investigation. These computational approaches enabled the prediction of the electronic properties of AM-6494 and CNP-520 plus their binding energies when complexed with BACE1. For AM-6494 and CNP-520 interaction with protonated BACE1, the ONIOM calculation gave binding free energy of −62.849 and −33.463 kcal/mol, respectively. In the unprotonated model, we observed binding free energy of −59.758 kcal/mol in AM-6494. Taken together thermochemistry of the process and molecular interaction plot, AM-6494 is more favourable than CNP-520 towards the inhibition of BACE1. The protonated model gave slightly better binding energy than the unprotonated form. However, both models could sufficiently describe ligand binding to BACE1 at the atomistic level. Understanding the detailed molecular interaction of these inhibitors could serve as a basis for pharmacophore exploration towards improved inhibitor design.

A theoretical study of 4-Mercaptobenzoic acid assembled on Ag for surface-enhanced raman scattering applications

Thiols are widely used in the preparation of self-assembled monolayers (SAMs) on metallic surfaces such as Ag, Cu and Au because of their strong affinity for such surfaces. These SAMs have various applications in nanotechnology and supramolecular chemistry. However, the chemistry of the metal surface and the thiol end is still vaguely understood, yet it fundamentally governs the properties of the SAMs. This paper reports density functional theory (DFT) and corroborating experimental findings focusing on vibrational Raman spectroscopy of Ag-Mercaptobenzoic acid (AgMBA) SAMs. The 4-MBA thiol was self-assembled onto Ag (111) and (100) fcc surfaces via both the COO- and S- ends. The experimental AgMBA vibrational frequencies showed the interaction of the 4-MBA with the Ag surface from both the S- and COO- atoms and the observation was supported by the our own n-layered integrated molecular orbital and molecular mechanics (ONIOM) calculated surface-enhanced Raman spectroscopy spectra and DFT thermodynamic calculations. The Ag(100)MBA self-assembled via the COO- end had the highest enthalpy of adsorption of -310.34 kJ/mol and it was the most stable plane contradicting the sulphur end consensus on previous papers. The adsorption of the 4-MBA moiety on the Ag surface was interplayed by the corrugation potential of the exposed surface and the thiol’s aromatic nature which resulted in the adsorption of 4-MBA predominately via the carbonyl end at slightly acidic pH conditions and a deprotonated thiol end.

Theoretical Determination of Size Effects in Zeolite-Catalyzed Alcohol Dehydration

In the upgrading of biomass pyrolysis vapors to hydrocarbons, dehydration accomplishes a primary objective of removing oxygen, and acidic zeolites represent promising catalysts for the dehydration reaction. Here, we utilized density functional theory calculations to estimate adsorption energetics and intrinsic kinetics of alcohol dehydration over H-ZSM-5, H-BEA, and H-AEL zeolites. The ONIOM (our Own N-layered Integrated molecular Orbital and molecular Mechanics) calculations of adsorption energies were observed to be inconsistent when benchmarked against QM (Quantum Mechanical)/Hartree–Fock and periodic boundary condition calculations. However, reaction coordinate calculations of adsorbed species and transition states were consistent across all levels considered. Comparison of ethanol, isopropanol (IPA), and tert-amyl alcohol (TAA) over these three zeolites allowed for a detailed examination of how confinement impacts on reaction mechanisms and kinetics. The TAA, seen to proceed via a carbocationic mechanism, was found to have the lowest activation barrier, followed by IPA and then ethanol, both of which dehydrate via a concerted mechanism. Barriers in H-BEA were consistently found to be lower than in H-ZSM-5 and H-AEL, attributed to late transition states and either elevated strain or inaccurately estimating long-range electrostatic interactions in H-AEL, respectively. Molecular dynamics simulations revealed that the diffusivity of these three alcohols in H-ZSM-5 were significantly overestimated by Knudsen diffusion, which will complicate experimental efforts to develop a kinetic model for catalytic fast pyrolysis.

Detailed investigation of N-(4-n-pentyl-oxybenzylidene)-4′-n-hexylaniline liquid crystal molecule

The study presents a comprehensive vibrational analysis of N-(4-n-pentyl-oxybenzylidene)-4′-n-hexylaniline liquid crystal molecule. The vibrational observations are supported by potential energy distribution analysis performed by VEDA. The optimized structure and the total electron density surface mapped with electrostatic potential were computed at the B3LYP/6–31 G level. A thorough comparative analysis of discernible modes, chemical reactivity, charge distribution, electrical properties, charge transfer, and hyperpolarizability was attempted using semi-empirical, Hartree-Fock, density functional theory and ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) computational methods for the mentioned molecule.

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

The complexes of selected long-chain arylpiperazines with homology models of 5-HT1A, 5-HT2A, and 5-HT7 receptors were investigated using quantum mechanical methods. The molecular geometries of the ligand–receptor complexes were firstly optimized with the Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) method. Next, the fragment molecular orbitals method with an energy decomposition analysis scheme (FMO-EDA) was employed to estimate the interaction energies in binding sites. The results clearly showed that orthosteric binding sites of studied serotonin receptors have both attractive and repulsive regions. In the case of 5-HT1A and 5-HT2A two repulsive areas, located in the lower part of the binding pocket, and one large area of attraction engaging many residues at the top of all helices were identified. Additionally, for the 5-HT7 receptor, the third area of destabilization located at the extracellular end of the helix 6 was found.

ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

AbstractThe crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4‐fluoro‐N‐(4‐(6‐(isopropylamino)pyrimidin‐4‐yl)thiazol‐2‐yl)‐N‐methylbenzamide (FITM, a negative allosteric modulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4 nM < IC50 > 10 000 nM) were investigated using quantum mechanical methods. The our own N‐layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize the molecular geometries of the receptor with complexed ligands, which were then used to perform the ab initio calculations using the fragment molecular orbitals method with energy decomposition analysis (FMO‐EDA). The results clearly showed that residues Q6603.28 and/or Y8056.55 were the anchoring points for all the studied analogs of FITM, while the H‐bond with T8157.38 determined only the orientation of very active molecules containing an amino substituent in the pyrimidine moiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic interactions mainly with L7575.44, F8016.51, or W7986.48. The applied ONIOM/FMO–EDA approach facilitated the study of effects related to very small changes in the ligand structure and led to conclusions regarding the significance of individual interactions in the allosteric binding pocket of mGluR1.

DNA and HSA interaction of Vanadium (IV), Copper (II), and Zinc (II) complexes derived from an asymmetric bidentate Schiff-base ligand: multi spectroscopic, viscosity measurements, molecular docking, and ONIOM studies.

The interaction of three complexes [Zn(II), Cu(II), and V(IV)] derived from an asymmetric bidentate Schiff-base ligand with DNA and HSA was studied using fluorescence quenching, UV-Vis spectroscopy, viscosity measurements, and computational methods[molecular docking and our Own N-layered Integrated molecular Orbital and molecular Mechanics(ONIOM)]. The obtained results revealed that the DNA and HSA affinities for binding of the synthesized compounds follow as V(IV)>Zn(II)>Cu(II) and Zn(II)>V(IV)>Cu(II), respectively. The distance between these compounds and HSA was obtained based on the Förster's theory of non-radiative energy transfer. Furthermore, computational molecular docking was carried out to investigate the DNA- and HSA-binding pose of the compounds. Molecular docking calculations showed that H-bond, hydrophobic, and π-cation interactions have dominant role in stability of the compound-HSA complexes. ONIOM method was utilized to investigate the HSA binding of the compounds more precisely in which molecular-mechanics method (UFF) and semi-empirical method (PM6) were selected for the low layer and the high layer, respectively. The results show that the structural parameters of the compounds changed along with binding, indicating the strong interaction between the compounds with HSA and DNA. Viscosity measurements as well as computational docking data suggest that all metal complexes interact with DNA, presumably by groove-binding mechanism.