Development of realistic models for Double Metal Cyanide catalyst active sites

Realistic molecular models of one and two-centre catalytic active sites originating from the cleavage of a precursor material known to give rise to an active double metal cyanide catalyst are described. Via periodic density functional calculations the structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes occurring at the surfaces of the precursor material. It is shown how these effects may be adequately captured by small molecular models of the active sites. The general methodology proposed should provide a computationally efficient basis for detailed future studies into catalytic reactions over double metal cyanide materials. Figure Reconstructed DMC [100]-surface: electrostatic potential mapped on charge density isosurface This work has been originally presented on the Modelling and Design of Molecular Materials conference in Wrocław, Poland.     

Electrostatic interactions play an essential role in DNA repair and cold-adaptation of Uracil DNA glycosylase

Life has adapted to most environments on earth, including low and high temperature niches. The increased catalytic efficiency and thermoliability observed for enzymes from organisms living in constantly cold regions when compared to their mesophilic and thermophilic cousins are poorly understood at the molecular level. Uracil DNA glycosylase (UNG) from cod (cUNG) catalyzes removal of uracil from DNA with an increased k_cat and reduced K_m relative to its warm-active human (hUNG) counterpart. Specific issues related to DNA repair and substrate binding/recognition (K_m) are here investigated by continuum electrostatics calculations, MD simulations and free energy calculations. Continuum electrostatic calculations reveal that cUNG has surface potentials that are more complementary to the DNA potential at and around the catalytic site when compared to hUNG, indicating improved substrate binding. Comparative MD simulations combined with free energy calculations using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method show that large opposing energies are involved when forming the enzyme-substrate complexes. Furthermore, the binding free energies obtained reveal that the Michaelis-Menten complex is more stable for cUNG, primarily due to enhanced electrostatic properties, suggesting that energetic fine-tuning of electrostatics can be utilized for enzymatic temperature adaptation. Energy decomposition pinpoints the residual determinants responsible for this adaptation. Figure Electrostatic isosurfaces of cod uracil DNA glycosylase in complex with double stranded DNA     

Pattern recognition based on color-coded quantum mechanical surfaces for molecular alignment

A pattern recognition algorithm for the alignment of drug-like molecules has been implemented. The method is based on the calculation of quantum mechanical derived local properties defined on a molecular surface. This approach has been shown to be very useful in attempting to derive generalized, non-atom based representations of molecular structure. The visualization of these surfaces is described together with details of the methodology developed for their use in molecular overlay and similarity calculations. In addition, this paper also introduces an additional local property, the local curvature (C _L), which can be used together with the quantum mechanical properties to describe the local shape. The method is exemplified using some problems representing common tasks encountered in molecular similarity. Figure Molecular surfaces for Lorazepam (left) and Diazepam (right)     

DFT tests for group 8 transition metal carbonyl complexes

The applicability of several popular density functionals in predicting the geometrical parameters and energetics of transition metal carbonyl complexes of iron, ruthenium and osmium has been studied. The methods tested include pure GGA functionals (BLYP, BP86, OPBE, HCTH, PBE, VSXC) and hybrid GGA functionals (B3PW91, B3LYP, PBE1PBE, MPW1K, B97-2, B1B95, PBE1KCIS). The effect of changing the metal basis set from Huzinaga’s all-electron basis to SDD scECP basis was also studied. The results show, that hybrid functionals are needed in order to describe the back-bonding ability of the carbonyl ligands as well as to deal with metal-metal bonds. The best general performance, when also the computational cost was considered, was obtained with hybrid functionals B3PW91 and PBE1PBE, which therefore provide an efficient tool for solving problems involving large or medium sized transition metal carbonyl compounds. Figure Optimized structure for one of the test molecules, the Ru₃(CO)₁₂ cluster, showing the staggered conformation of the carbonyl ligands     

3D–QSAR studies of orvinol analogs as κ-opioid agonists

Orvinols are potent analgesics that target opioid receptors. However, their analgesic mechanism remains unclear and no significant preference for subtype opioid receptor has been achieved. In order to find new orvinols that target the κ-receptor, comparative 3D–QSAR studies were performed on 26 orvinol analogs using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The best predictions for the κ-receptor were obtained with the CoMFA standard model (q ²=0.686, r ²=0.947) and CoMSIA model combined steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields (q ²=0.678, r ²=0.914). The models built were further validated by a test set made up of seven compounds, leading to predictive r ² values of 0.672 for CoMFA and 0.593 for CoMSIA. The study could be helpful for designing and prepare new category κ-agonists from orvinols.      

Structure-based 3D-QSAR studies on thiazoles as 5-HT<Subscript>3</Subscript> receptor antagonists

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT₃ receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT_3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT₃ receptor antagonists.      

Improved electrostatic properties using combined Mulliken and hybridization-displaced charges for radicals

Effects of explicit consideration of charges displaced from atomic sites due to atomic orbital hybridization called hybridization-displaced charges (HDC) on dipole moments and surface molecular electrostatic potentials of certain radicals and their complexes with closed-shell molecules have been studied. HDC were computed for several radicals and their complexes at the B3LYP/6–31G** level of theory. At this level, HDC consist of three point charges associated with hydrogen atoms and seven point charges associated with heavy atoms belonging to the second row of the periodic table. HDC are so calculated that the contribution of each atom to the component of molecular dipole moment arising due to atomic orbital hybridization is preserved. It is found that dipole moments and electrostatic potentials of the systems studied here can be obtained with a significantly improved accuracy using a combination of Mulliken charges and HDC over that obtained by Mulliken charges only. Figure Surface MEP map of H₂O-HO· radical complex obtained using Mulliken charges combined with HDC     

A density functional study towards substituent effects on anion sensing with urea receptors

Effects of substituents on anion binding in different urea based receptors have been examined using density functional (B3LYP/6-311+G**) level of theory. The complexes formed by a variety of substituted urea with a halide anion (fluoride) and an oxy-anion (acetate) have been calculated. The stronger complexes were predicted for receptors with fluoride ion than that of acetate ion, however, in water the preference was found to be reversed. The pK _a calculations showed the preferred sites of deprotonation for positional isomers, while interacting with anions. The position of the substituent in the receptor, however, could change the preferred sites of deprotonation compared to the site predicted with pK _a values.      

The structure of 5a,6–anhydrotetracycline and its Mg2+ complexes in aqueous solution

Semiempirical molecular orbital theory has been used for a systematic scan of the binding positions for a Mg²⁺ ion with 5a,6–anhydrotetracycline taking both conformational flexibility and possible different tautomeric forms into account. The magnesium ion has been calculated alone and with four or five complexed water molecules in order to simulate the experimental situation more closely. The results are analyzed by comparing the behavior of the title compound with that of tetracycline itself and possible causes for the stronger induction of the Tetracycline Receptor (TetR) by 5a,6–anhydrotetracycline than by tetracycline are considered. Energetically favored 3D -structure of the zwitteranionic 5a,6-anhydrotetracycline magnesium complex in solution Electronic Supplementary Material Supplementary material is available for this article at     

Why are dimethyl sulfoxide and dimethyl sulfone such good solvents?

We have carried out B3PW91 and MP2-FC computational studies of dimethyl sulfoxide, (CH₃)₂SO, and dimethyl sulfone, (CH₃)₂SO₂. The objective was to establish quantitatively the basis for their high polarities and boiling points, and their strong solvent powers for a variety of solutes. Natural bond order analyses show that the sulfur–oxygen linkages are not double bonds, as widely believed, but rather are coordinate covalent single S⁺→O⁻ bonds. The calculated electrostatic potentials on the molecular surfaces reveal several strongly positive and negative sites (the former including σ-holes on the sulfurs) through which a variety of simultaneous intermolecular electrostatic interactions can occur. A series of examples is given. In terms of these features the striking properties of dimethyl sulfoxide and dimethyl sulfone, their large dipole moments and dielectric constants, their high boiling points and why they are such good solvents, can readily be understood. Figure Dimers of dimethyl sulfoxide (DMSO; left) and dimethyl sulfone (DMSO2; right) showing O S—O -hole bonding and C H—O hydrogen bonding. Sulfur atoms are yellow, oxygens are red, carbons are gray and hydrogens are white     

Halogen bonding and the design of new materials: organic bromides, chlorides and perhaps even fluorides as donors

In some halides RX, the halogen X has a region of positive electrostatic potential on its outermost portion, centered around the extension of the R−X bond. The electrostatic attraction between this positive region and a lone pair of a Lewis base is termed halogen bonding. The existence and magnitudes of such positive potentials on some covalently bonded halogens, and the characteristic directionality of the interaction, can be explained in terms of the degree of sp hybridization and polarizability of X and the electronegativity of R. Halogen bonding increases in strength in the order Cl < Br < I; fluorine is frequently said to not form halogen bonds, although a notable result of the present study is computational evidence that it does have the capability of doing so, if R is sufficiently electron withdrawing. An increasingly important application of halogen bonding is in the design of new materials (e.g., crystal engineering). In this paper, we present the calculated energies of a series of halogen-bonding interactions that could be the basis for forming linear chains, of types X----X----X---- or X----Y----X----Y----. We focus upon chlorides and bromides, and nitrogen bases. The B3PW91/6-311G(3df,2p) and MP2/6-311++G(3df,2p) procedures were used. We show how the computed electrostatic potentials (B3PW91/6-31G**) can provide guidance in selecting appropriate halide/base pairs. Figure Computed electrostatic potential of CH₃CH₂Br on the molecular surface defined by the 0.001-au contour of the electronic density. The bromine is facing the reader, and has a small positive (green) region centered around the intersection of the C–Br axis with the surface     

Ion pair aggregates and reactions; experiment and theory

Two methods have been developed for determining the aggregation equilibrium constants of lithium enolates based on the change in UV-vis spectrum with concentration and the effect of aggregation on proton-transfer equilibria. Dimers and tetramers are common. Substitution α to the carbonyl group generally reduces aggregation. Kinetic studies show that S_N2 alkylations generally occur with the monomers, even in the presence of large amounts of aggregate. The qualitative chemistry is well modeled by ab initio computations at the HF level with modest basis sets; in these studies solvation is modeled by a combination of coordination of lithium cation with an ether oxygen and the electrostatic interaction of the resulting dipoles and quadrupoles with the solvent dielectric continuum. This review is based on the fifth annual Paul vR Schleyer Lecture presented at Professor Schleyer's 75th birthday symposium, Athens GA, Feb 26, 2005. Carbon Acidity 123. For no. 122 see Streitwieser A, Kaufman MJ, Bors DA, MacArthur CA, Murphy JT, Guibe F, Arkivoc (2005) (vi) 200–210Dedicated to Professor Dr. Paul von Ragué Schleyer on the occasion of his 75th birthday     

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K _i =6 nM) but a low affinity with cyclin-dependent kinase 4 (K _i =1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4. Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by LIGPLOT.      

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P<Superscript>III</Superscript>)

Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (P^III). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that decomposition to P^III derivatives proceeds via an elimination reaction. Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (P^III)     

3D-QSAR and docking studies of 3-arylquinazolinethione derivatives as selective estrogen receptor modulators

3D-QSAR and molecular docking analysis were performed to explore the interaction of estrogen receptors (ERα and ERβ) with a series of 3-arylquinazolinethione derivatives. Using the conformations of these compounds revealed by molecular docking, CoMFA analysis resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity relationship (QSSR) models predicting the inhibitory activity against ERβ and the selectivity against ERá. The q² and R² values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting both the inhibitory activity and selectivity of 3-arylquinazolinethione derivatives for these protein targets. A set of 3D contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal modifications of substituents at C2 and C5 of the quinazoline which my be useful to improve both the activity and selectivity of ERβ/ ERα. Results showed that both the steric and electrostatic factors should appropriately be taken into account in future rational design and development of more active and more selective ERβ inhibitors for the therapeutic treatment of osteoporosis. Figure Structures of ERβ binding with compounds 1aar, 1ax and 1aag obtained from molecular docking     

Model of the whole rat AT1 receptor and the ligand-binding site

We present a three-dimensional model of the rat type 1 receptor (AT₁) for the hormone angiotensin II (Ang II). Ang II and the AT₁ receptor play a critical role in the cell-signaling process responsible for the actions of renin–angiotensin system in the regulation of blood pressure, water-electrolyte homeostasis and cell growth. Development of improved therapeutics would be significantly enhanced with the availability of a 3D-structure model for the AT₁ receptor and of the binding site for agonists and antagonists. This model was constructed using a combination of computation and homology-modeling techniques starting with the experimentally determined three-dimensional structure of bovine rhodopsin (PDB#1F88) as a template. All 359 residues and two disulfide bonds in the rat AT₁ receptor have been accounted for in this model. Ramachandran-map analysis and a 1 nanosecond molecular dynamics simulation of the solvated receptor with and without the bound ligand, Ang II, lend credence to the validity of the model. Docking calculations were performed with the agonist, Ang II and the antihypertensive antagonist, losartan.      

ParaFrag—an approach for surface-based similarity comparison of molecular fragments

A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IE_L), local electron affinity (EA_L) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail. Figure Encoding surface hotspots as a ParaFrag pharmacophore