Computational study of fluoroquinolone binding to and its applicability to future drug design

Fluoroquinolones are an important therapeutic class in the targeting of new and resistant bacterial infections. Fluoroquinolones bind to bacterial type II topoisomerase via a water‐Mg²⁺ bridge. However, binding to magnesium‐containing molecules outside of the target cells increases the minimum inhibitory concentration (MIC) and promotes drug resistance. As a result, fluoroquinolones are counter‐indicated with magnesium and multivalent metal cation containing drugs, such as antacids. The antibiotic efficacy of fluoroquinolones has also been shown to be pH dependent, as we show the effect of protonation state on magnesium binding. This work presents a systematic computational study of fluoroquinolones' magnesium‐binding properties. We use B3LYP density functional theory and triple‐zeta basis sets, to evaluate binding affinities. Complexation is predicted to be thermodynamically favorable at neutral and basic compared to acidic pH. The calculated complexation energies broadly capture experimental binding affinities, suggesting this is a valid approach for designing new fluoroquinolones with a target magnesium binding affinity. We also investigate the effect of chemical substitution at the carboxylic acid to help in the identification of potential new antibiotics based on the fluoroquinolone pharmacophore.     

Displacement affinity chromatography of protein phosphatase one (PP1) complexes

Background  

Protein phosphatase one (PP1) is a ubiquitously expressed, highly conserved protein phosphatase that dephosphorylates target protein serine and threonine residues. PP1 is localized to its site of action by interacting with targeting or regulatory proteins, a majority of which contains a primary docking site referred to as the RVXF/W motif.     

Simulating periodic trends in the structure and catalytic activity of coinage metal nanoribbons

We present a systematic density functional theory (DFT) study of the structure and catalytic activity of group 10 (Ni, Pd, Pt) and group 11 (Cu, Ag, Au) coinage metal nanoribbons. These infinite, periodic, quasi‐one‐dimensional structures are conceptually important as intermediates between small metal clusters and close‐packed metal surfaces, and have been shown experimentally to be practical catalysts. We find that nanoribbons have significantly higher predicted H₂ dissociation activity than close‐packed metal surfaces consistent with their lower coordination numbers. Computed periodic trends are reasonable, with late transition states and low barriers for H₂ dissociation over late group 10 nanoribbons, suggesting their promise as practical catalysts. These trends are consistent with the isolated nanoribbons' computed molecular electrostatic potentials. Calculations also predict nearly linear Brønsted–Evans–Polanyi relationships between the nanoribbons' H₂ dissociation energies and dissociation barriers. We also test new meta‐generalized gradient approximation (GGA) and hybrid DFT approximations for H₂ dissociation over these nanoribbons. These new functionals increase the (generally underestimated) dissociation barriers predicted by standard GGAs, motivating their continued application in surface chemistry. © 2015 Wiley Periodicals, Inc.     

Interactions of ibuprofen with hybrid lipid bilayers probed by complementary surface-enhanced vibrational spectroscopies

The incorporation of small molecules into lipid bilayers is a process of biological importance and clinical relevance that can change the material properties of cell membranes and cause deleterious side effects for certain drugs. Here we report the direct observation, using surface-enhanced Raman and IR spectroscopies (SERS, SEIRA), of the insertion of ibuprofen molecules into hybrid lipid bilayers. The alkanethiol-phospholipid hybrid bilayers were formed onto gold nanoshells by self-assembly, where the underlying nanoshell substrates provided the necessary enhancements for SERS and SEIRA. The spectroscopic data reveal specific interactions between ibuprofen and phospholipid moieties and indicate that the overall hydrophobicity of ibuprofen plays an important role in its intercalation in these membrane mimics.     

p-Substituted Tris(2-pyridylmethyl)amines as Ligands for Highly Active ATRP Catalysts: Facile Synthesis and Characterization

A facile and efficient two-step synthesis of p-substituted tris(2-pyridylmethyl)amine (TPMA) ligands to form Cu complexes with the highest activity to date in atom transfer radical polymerization (ATRP) is presented. In the divergent synthesis, p-Cl substituents in tris(4-chloro-2-pyridylmethyl)amine (TPMA^3Cl) were replaced in one step and high yield by electron-donating cyclic amines (pyrrolidine (TPMA^PYR), piperidine (TPMA^PIP), and morpholine (TPMA^MOR)) by nucleophilic aromatic substitution. The [Cu^II(TPMA^NR2)Br]⁺ complexes exhibited larger energy gaps between frontier molecular orbitals and >0.2 V more negative reduction potentials than [Cu^II(TPMA)Br]⁺, indicating >3 orders of magnitude higher ATRP activity. [Cu^I(TPMA^PYR)]⁺ exhibited the highest reported activity for Br-capped acrylate chain ends in DMF, and moderate activity toward C−F bonds at room temperature. ATRP of n-butyl acrylate using only 10–25 part per million loadings of [Cu^II(TPMA^NR2)Br]⁺ exhibited excellent control.     

Using molecular similarity to construct accurate semiempirical electronic structure theories

Ab initio electronic structure methods give accurate results for small systems, but do not scale well to large systems. Chemical insight tells us that molecular functional groups will behave approximately the same way in all molecules, large or small. This molecular similarity is exploited in semiempirical methods, which couple simple electronic structure theories with parameters for the transferable characteristics of functional groups. We propose that high-level calculations on small molecules provide a rich source of parametrization data. In principle, we can select a functional group, generate a large amount of ab initio data on the group in various small-molecule environments, and "mine" this data to build a sophisticated model for the group's behavior in large environments. This work details such a model for electron correlation: a semiempirical, subsystem-based correlation functional that predicts a subsystem's two-electron density matrix as a functional of its one-electron density matrix. This model is demonstrated on two small systems: chains of linear, minimal-basis (H-H)(5), treated as a sum of four overlapping (H-H)(2) subsystems; and the aldehyde group of a set of HOC-R molecules. The results provide an initial demonstration of the feasibility of the approach.     

Surface enhanced Raman optical activity of molecules on orientationally averaged substrates: theory of electromagnetic effects

We present a model for electromagnetic enhancements in surface enhanced Raman optical activity (SEROA) spectroscopy. The model extends previous treatments of SEROA to substrates, such as metal nanoparticles in solution, that are orientationally averaged with respect to the laboratory frame. Our theoretical treatment combines analytical expressions for unenhanced Raman optical activity with molecular polarizability tensors that are dressed by the substrate's electromagnetic enhancements. We evaluate enhancements from model substrates to determine preliminary scaling laws and selection rules for SEROA. We find that dipolar substrates enhance Raman optical activity (ROA) scattering less than Raman scattering. Evanescent gradient contributions to orientationally averaged ROA scale to first or higher orders in the gradient of the incident plane-wave field. These evanescent gradient contributions may be large for substrates with quadrupolar responses to the plane-wave field gradient. Some substrates may also show a ROA contribution that depends only on the molecular electric dipole-electric dipole polarizability. These conclusions are illustrated via numerical calculations of surface enhanced Raman and ROA spectra from (R)-(-)-bromochlorofluoromethane on various model substrates.     

Chemo- and regioselective cyclohydrocarbonylation of alpha-keto alkynes catalyzed by a zwitterionic rhodium complex and triphenyl phosphite

alpha-Keto alkynes react with CO and H(2) in the presence of catalytic quantities of the zwitterionic rhodium complex (eta(6)-C(6)H(5)BPh(3))(-)Rh(+)(1,5-COD) and triphenyl phosphite affording either the 2-, 2(3H)-, or 2(5H)-furanones in 61-93% yields. The cyclohydrocarbonylation is readily accomplished using substrates containing alkyl, aryl, vinyl, and alkoxy groups at the acetylenic terminal, as well as a variety of primary, secondary, and tertiary alkyl, aryl, and heteroaryl groups connected to the ketone functionality. Structural and electronic properties present in the starting materials mediate the chemo- and regioselectivity of the reaction.     

Synthesis,characterization, and computational modeling of benzodithiophene donor–acceptor semiconducting polymers

Donor–acceptor semiconducting polymers containing benzodithiophene with decyl phenylethynyl substituents have been synthesized. Density functional calculations on the polymers' band gaps and frontier orbitals energies provide reasonable agreement with cyclic voltammetry, photoelectron spectroscopy, and UV–vis absorption measurements. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Parameterized local hybrid functionals from density-matrix similarity metrics

We recently proposed a real-space similarity metric comparing the Kohn-Sham one-particle density matrix to the local spin-density approximation model density matrix [Janesko and Scuseria, J. Chem. Phys. 127, 164117 (2007)]. This metric provides a useful ingredient for constructing local hybrid density functionals that locally mix exact exchange and semilocal density functional theory exchange. Here we present two lines of inquiry: An approximate similarity metric comparing exact versus generalized gradient approximation (GGA), exchange and parameterized mixing functions using these similarity metrics. This approach yields significantly improved thermochemistry, including GGA local hybrids whose thermochemical performance approaches GGA global hybrids.