Abstracts of Referred Papers

Imidazole-containing Farnesyltransferase Inhibitors: 3D Quantitative Structure-activity Relationship and Molecular Docking Studies

A. Xie, S. Odde, P. Sivaprakasam and R. J. Doerksen, 23, 431-448 (2009). DOI:10.1007/s10822-009-9278-z

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Topological polar surface area (TPSA), which makes use of functional group contributions based on a large database of structures, is a convenient measure of the polar surface area that avoids the need to calculate ligand 3D structure or to decide which is the relevant biological conformation or conformations. We demonstrate the utility of TPSA in 2DQSAR for 14 sets of diverse pharmacological activity data. Even though a large pool of reports showing the importance of the classic 2D descriptors such as calculated logP (ClogP) and calculated molar refractivity (CMR) exists in the 2DQSAR literature, this is the first report to demonstrate the value of TPSA as a relevant descriptor applicable to a large, structurally and pharmacologically diverse set of classes of compounds. We also address the limitations of applicability of this descriptor for 2D-QSAR analysis. We observed a negative correlation of TPSA with activity data for anticancer alkaloids, MT1 and MT2 agonists, MAO-B and tumor necrosis factor-α inhibitors and a positive correlation with inhibitory activity data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria, trypanosomatids and CB2 agonists.

Probing the physicochemical and structural requirements for glycogen synthase kinase-3a inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides

Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral ß-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3ß) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC50 0.7–1.0 µM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.

2-N-Methyl modifications and SAR studies of manzamine A

Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral ß-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3ß) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC50 0.7–1.0 µM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.

Stereoelectronic Properties of Spiroquinazolinones in Differential PDE7 Inhibitory Activity

P. R. Daga and R. J. Doerksen Journal of Computational Chemistry, 29,1945-1954 (2008). DOI:10.1002/jcc.20960

A detailed computational study on a series of spiroquinazolinones showing phosphodiesterase 7 (PDE7) inhibitory activity was performed to understand the binding mode and the role of stereoelectronic properties in binding. Our docking studies reproduced the essential hydrogen bonding and hydrophobic interactions for inhibitors of this class of enzymes. The N1 proton of the quinazolinone scaffold was involved in H-bonding to an amide side chain of the conserved glutamine residue in the active site. The central bicyclic ring of the molecules showed hydrophobic and -stacking interactions with hydrophobic and aromatic amino acid residues, respectively, present in the PDE7 active site. The docked conformations were optimized with density functional theory (DFT) and DFT electronic properties were calculated. Comparison of molecular electrostatic potential (MEP) plots of inhibitors with the active site of PDE7 suggested that the electronic distribution in the molecules is as important as steric factors for binding of the molecules to the receptor. The hydrogen bonding ability and nucleophilic nature of N1 appeared to be important for governing the interaction with PDE7. For less active inhibitors (pIC50 < 6.5), the MEP maximum at N1 of the spiroquinazolinone ring was high or low based on the electronic properties of the substituents. All the more active molecules (pIC50 > 6.5) had MEP highest at N3, not N1. Efficient binding of these inhibitors may need some rearrangement of side chains of active-site residues, especially Asn365. This computational modeling study should aid in design of new molecules in this class with improved PDE7 inhibition. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008

Structure Assignment and Actin Docking of a Latrunculin with a Highly Oxidized Thiazolidinone Ring

S. A. Ahmed, S. Odde, P. R. Daga, J. J. Bowling, M. K. Mesbah, D. T. Youssef, S. I. Khalifa, R. J. Doerksen and M. T. Hamann Organic Letters, 9, 4773-4776 (2007). DOI:10.1021/ol7020675

A new latrunculin, oxalatrunculin B (3), was isolated from Red Sea sponge Negombata corticata. Extensive spectroscopic analysis revealed an unprecedented heterocycle in which the rare thiazolidinone ring found in latrunculins was oxidized with three additional oxygens. An actin polymerization inhibition assay agreed with MM-PBSA free energy calculations that 3 binds more weakly than latrunculin B to actin. Significant antifungal and anticancer activity of 3 was found, suggesting an alternate target in addition to actin for latrunculin bioactivity.

"Probing the physicochemical and structural requirements for glycogen synthase kinase-3alpha inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides,"

P. Sivaprakasam, A. Xie and R. J. Doerksen Bioorganic & Medicinal Chemistry, 14, 8210-8218 (2006). DOI:10.1016/j.bmc.2006.09.021

Glycogen synthase kinase-3α (GSK-3α) was recently found to be an attractive target for the treatment of Alzheimer’s disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3α binding. Using Fujita–Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3α inhibition.

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2, 5-diaminobenzophenone scaffold

A. Xie, P. Sivaprakasam and R. J. Doerksen Bioorganic & Medicinal Chemistry, 14, 7311 (2006). DOI:10.1016/j.bmc.2006.06.041

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r2 = 0.94, q2 = 0.63, and . The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.

Biomimetic facially amphiphilic antibacterial oligomers with conformationally stiff backbones

H. Tang; R. J. Doerksen; T. V. Jones; M. L. Klein; G. N. Tew Chemistry & Biology, 13, 427-435 (2006). DOI:/10.1016/j.chembiol.2006.02.007

A foldamer has been designed with a conformationally stiff backbone that is facially amphiphilic. The oligomer has excellent antimicrobial activity and was found to be 18 times more active toward bacterial cells than human red blood cells. The oligomer is built from arylamide bonds around a central 4,6-dicarboxy pyrimidine ring. The conformation was studied by X-ray crystallography and solution NMR spectroscopy. Density-functional (DFT) calculations were performed to guide the design. These calculations accurately predicted the overall conformation as well as NMR chemical shifts. Antibacterial activity was demonstrated against E. coli, a gram-negative strain, and B. subtilis, a gram-positive strain. The minimal inhibitory concentration is 0.8 μg/ml.

Advances in methods and algorithms in a modern quantum chemistry program package

Y. Shao; L. Fusti-Molnar; Y. Jung; J. Kussmann; C. Ochsenfeld; S. T. Brown; A. T. B. Gilbert; L. V. Slipchenko; S. V. Levchenko; D. P. O'Neill; R. A. Distasio Jr.; R. C. Lochan; T. Wang; G. J. O. Beran; N. A. Besley; J. M. Herbert; C. Y. Lin; T. Van Voorhis; S. H. Chien; A. Sodt; R. P. Steele; V. A. Rassolov; P. E. Maslen; P. P. Korambath; R. D. Adamson; B. Austin; J. Baker; E. F. C. Byrd; H. Dachsel; R. J. Doerksen; A. Dreuw; B. D. Dunietz; A. D. Dutoi; T. R. Furlani; S. R. Gwaltney; A. Heyden; S. Hirata; C.-P. Hsu; G. Kedziora; R. Z. Khalliulin; P. Klunzinger; A. M. Lee; M. S. Lee; W. Liang; I. Lotan; N. Nair; B. Peters; E. I. Proynov; P. A. Pieniazek; Y. M. Rhee; J. Ritchie; E. Rosta; C. D. Sherrill; A. C. Simmonett; J. E. Subotnik; H. L. Woodcock III; W. Zhang; A. T. Bell; A. K. Chakraborty; D. M. Chipman; F. J. Keil; A. Warshel; W. J. Hehre; H. F. Schaefer III; J. Kong; A. I. Krylov; P. M. W. Gill; M. Head-Gordon Physical Chemistry Chemical Physics, 8, 3172-3191 (2006). Invited article. Top 10 most downloaded PCCP articles in August 2006 DOI:10.1039/b517914a

Advances in theory and algorithms for electronic structure calculations must be incorporated into program packages to enable them to become routinely used by the broader chemical community. This work reviews advances made over the past five years or so that constitute the major improvements contained in a new release of the Q-Chem quantum chemistry package, together with illustrative timings and applications. Specific developments discussed include fast methods for density functional theory calculations, linear scaling evaluation of energies, NMR chemical shifts and electric properties, fast auxiliary basis function methods for correlated energies and gradients, equation-of-motion coupled cluster methods for ground and excited states, geminal wavefunctions, embedding methods and techniques for exploring potential energy surfaces.

Controlling the conformation of arylamides: Computational studies of intramolecular hydrogen bonds between amides and ethers or thioethers

The role of an ortho-alkylthioether group to control the conformation around the ring-N bonds of meta-connected arylamide oligomers is studied. Density functional theory (DFT) geometries of model compounds, including acetanilide, ether and thioether acetanilide, and their corresponding diamides, show that for either monoamide or diamide the alkyl sidechain of the thioether should be perpendicular to the aryl plane, whereas for the ether monoamide, the alkyl sidechain is in the aryl plane. DFT ring-N torsional potentials and constrained geometries of the model compounds demonstrate that carbonyl-S repulsion leads to a high torsional barrier and that intramolecular N-H...S and C-H...O hydrogen bonds and ring-amide conjugation lead to N-H having a preferred orientation in the benzene plane pointing towards S. N-H lengthens and the ortho ring C-H shortens in a regular pattern in the approach to the preferred orientation. Calculated infrared frequencies for the N-H stretch show a clear red-shift between model compounds without and with the thioether sidechain.

Synthesis of urea oligomers and their antibacterial activity

Facially amphiphilic urea oligomers were successfully prepared in a one-pot reaction by carbonyl diimidazole (CDI) coupling and showed greater antibacterial activity against both Gramnegative Escherichia coli and Gram-positive Bacillus subtilis than MSI-78.

Nontoxic membrane-active antimicrobial arylamide oligomers

This is a communication (no abstract).

Keywords: amphiphiles; antimicrobial agents; aryl amides; oligomers; peptides.

Novel conformationally-constrained beta-peptides characterized by ¹H NMR chemical shifts

Novel oxanorbornene beta-peptides were synthesized and shown, by ¹H NMR calculations which agree with experimental data, to form consecutive 8-membered hydrogen-bonded ring helices for both dimer and trimer.

Intramolecular hydrogen bonds: Ab initio Car-Parrinello simulations of arylamide torsions

Gas-phase, room temperature Car-Parrinello molecular dynamics simulations using the HCTH density functional are reported for the arylamides acetanilide (1) and ortho-methylthioacetanilide (2). The simulations show that in 1, rotation around the ring.amide bond is relatively unrestricted. By contrast, in 2 the methylthio side chain encourages the amide to be directed with N-H pointing toward S, not to flip by 360�, and furthermore to remain close to coplanar with the benzene ring. Because of an intramolecular N-H...S hydrogen bond, the N-H stretch frequency of 2 is red-shifted by ~78 cm^-1 compared to that of 1.

Bond orders and polarizabilities as measures of aromaticity: Azines, azoles, oxazoles, and thiazoles

Recent interest in quantitative aromaticity indices has focussed on structural, magnetic, and energetic criteria. In this work, aromaticity indices based on polarizabilities are compared with indices based upon bond orders for benzene and 12 azines, pyrrole and 9 azoles, furan and 9 oxazoles, and thiophene and 8 thiazoles. The best polarizability-based index of aromaticity we find is the polarizability anisotropy of the pi-electrons. However, none of the indices constructed from polarizabilities seem to be entirely suitable as measures of aromaticity. The comparison of the structural and polarizability scales enables us to formulate three critical tests that can be used to eliminate quickly unsuitable aromaticity scales for this set of heterocycles.

De novo design of biomimetic antimicrobial polymers

The design of polymers and oligomers that mimic the complex structures and remarkable biological properties of proteins is an important endeavor with both fundamental and practical implications. Recently, a number of nonnatural peptides with designed sequences have been elaborated to provide biologically active structures; in particular, facially amphiphilic peptides built from beta-amino acids have been shown to mimic both the structures as well as the biological function of natural antimicrobial peptides such as magainins and cecropins. However, these natural peptides as well as their beta-peptide analogues are expensive to prepare and difficult to produce on a large scale, limiting their potential use to certain pharmaceutical applications. We therefore have designed a series of facially amphiphilic arylamide polymers that capture the physical and biological properties of this class of antimicrobial peptides, but are easy to prepare from inexpensive monomers. The design process was aided by molecular calculations with density functional theory-computed torsional potentials. This new class of amphiphilic polymers may be applied in situations where inexpensive antimicrobial agents are required.

Bond orders in heteroaromatic rings

Bond orders are calculated at the Hartree-Fock and 2nd-order, M{\o}ller-Plesset (MP2) level for 324 distinct ring bonds in 60 heterocyclic molecules. These include benzene and 12 azines, pyrrole and 9 azoles, furan and 9 oxazoles, thiophene and 8 thiazoles, boroxine, trioxadiborole, borazine and 9 azaborinines, 3 azaboroles, and 3 oxazaboroles. The correlated bond orders are generally, but not always, smaller than their Hartree-Fock counterparts. Gordy bond orders differ from the ab initio ones by large amounts. A plot of MP2 bond orders versus bond lengths shows clearly that an empirical Gordy type relationship cannot be very accurate. Some trends in bond orders are identified.

Quadrupole and octopole moments of heteroaromatic rings

Ab initio, second-order, Møller-Plesset perturbation theory calculations of quadrupole and octopole moments are reported for 36 different 6-pi-electron monocycles: benzene, 12 azines, pyrrole, 9 azoles, furan, 9 oxazoles, borazine, boroxine and 1,2,4,3,5-trioxadiborole. Agreement with the limited experimental and computational data available is generally good.

Structures, vibrational frequencies and polarizabilities of diazaborinines, triazadiborinines, azaboroles, and oxazaboroles

Ab initio, second-order, Møller-Plesset perturbation theory calculations of the equilibrium geometries, harmonic vibrational frequencies, relative stabilities, dipole moments, and static dipole polarizabilities are reported for 70 different 6-pi-electron monocycles containing boron and nitrogen. These include 26 azaborinines isosteric to pyridine, 16 azaboroles, and 28 oxazaboroles. The most stable isomers have the substructure XBHNH, where X = N, NH, or O is the base-ring heteroatom. Planar conformations are stable minima for all but 15 five-membered rings. Lower level calculations are unreliable in predicting which molecules are planar. Good agreement is found with the available electron diffraction and X-ray structures of substituted rings. Additive atom and bond polarizability models which are accurate to within a few percent are constructed for a larger set of 104 planar molecules, including azines, azoles, oxazoles, and azaborinines isosteric to benzene. The presence of boron causes scatter of the polarizabilities of isomers; hence the additive models of polarizability are less accurate than if only heterocycles containing C, N, and O are included.

Geometries and multipole moments of AlH₄^-, SiH₄, PH₃, H₂S and HCl

Robert J. Doerksen, Ajit J. Thakkar, Toshikatsu Koga and Minako Hayashi

Theochem 488, 217 (1999).- DOI: 10.1016/S0166-1280(99)00020-2

Second-order, Møller-Plesset, perturbation theory geometry optimizations for AlH₄^-, SiH₄, PH₃, H₂S and HCl are performed with [11s8p2d1f] and [11s8p3d2f1g] basis sets of contracted Gaussian-type functions. The electric dipole, quadrupole and octopole moments of these molecules are computed at the predicted equilibrium geometries. The calculated geometries and multipole moments are in fine agreement with previous experimental results and computations of sufficiently high quality. The calculated octopole moments are the only ones available for three of these molecules.

Azaborinines: structures, vibrational frequencies and polarizabilities

Ab initio second-order Møller-Plesset (MP2) perturbation theory calculations of the equilibrium geometries, relative stabilities, harmonic vibrational frequencies, dipole moments and static dipole polarizabilities are reported for all 17 possible azaborinines (commonly called azaborines) of the formula C_6-2nH₆B_nN_n, n=1,2,3. Planar conformations are stable minima for 16 of these molecules; some errors in the literature on this point are corrected. The most stable isomers for n=1, 2 and 3 respectively are 1,2-azaborinine, 1,3,2,4-diazadiborinine and borazine. Good agreement is found with available X-ray structures of substituted azaborinines. The ratio of MP2 to Hartree-Fock (HF) harmonic frequencies is found to vary around an average of 0.95 for this set of isoelectronic molecules. The polarizabilities of the azaborinines along with our earlier results for the azoles, oxazoles and azines constitute a uniform quality data set of polarizabilities for 50 heteroaromatic molecules. Simple empirical formulas based upon atom- and bond-additive models correlate the calculated polarizabilities of the 49 planar heteroaromatic rings quite well.

Polarizabilities of heteroaromatic molecules: azines revisited

Ab initio, electron correlated calculations of the equilibrium geometries, dipole moments and static dipole polarizabilities are reported for benzene and twelve heteroaromatic six-membered rings obtained from it by aza-substitution. Our geometries and dipole moments agree well with available experimental microwave determinations. The polarizabilities are in reasonable agreement with the fragmentary experimental data available. Uncoupled Hartree-Fock calculations indicate that as much as half the polarizability comes from the sigma electrons. Simple empirical formulas based upon atom- and bond-additive models correlate the calculated polarizabilities of 33 five- and six-membered heteroaromatic rings (10 azoles, 10 oxazoles, 13 azines) quite well. The correlation improves significantly if systematic data of uniform quality are used.

Polarizabilities of oxazoles: ab initio calculations and simple models

Ab initio, electron correlated calculations of the equilibrium geometries, dipole moments and static dipole polarizabilities are reported for ten heteroaromatic five-membered rings: furan, oxazole, isoxazole, all four oxadiazoles, both oxatriazoles, and oxatetrazole. Our geometries and dipole moments agree well with available experimental microwave determinations. The polarizabilities are expected to be accurate to within 5%. Structural isomerism affects the dipole moments strongly but the dipole polarizabilities are rather insensitive to it. Uncoupled Hartree-Fock calculations indicate that as much as half the polarizability comes from the pi electrons. Simple empirical formulas based upon atom- and bond-additive models correlate the calculated polarizabilities of 20 five-membered heteroaromatic rings (10 azoles and 10 oxazoles) quite well.

Polarizabilities of aromatic five-membered rings: azoles

Ab initio, electron correlated calculations of dipole moments and static dipole polarizabilities are reported for ten heteroaromatic five-membered rings: pyrrole, pyrazole, imidazole, all four triazoles, both tetrazole tautomers, and the hypothetical pentazole. They are expected to be accurate to within 5%. Structural isomerism affects the dipole moments strongly but the dipole polarizabilities are rather insensitive to it. Uncoupled Hartree-Fock calculations indicate that only about half the polarizability comes from the pi electrons. Simple empirical formulas correlate the calculated polarizabilities quite well. Aromaticity scales based on polarizabilities are discussed.

Joint computational-experimental approach to effective and selective antimicrobial oligomers.

In a project to mimic and expand upon naturally-occurring amphiphilic antimicrobial defense peptides, a joint experimental-computational approach was used to design, synthesize, test, and then improve novel antibacterial compounds. On the computational side, calculated density-functional theory (DFT) relative stabilities of many designed backbones and sidechains, simulations using a force field with DFT-modified torsional potentials, amide vibrational frequencies and chemical shifts, and Car-Parrinello molecular dynamics simulations predicted the overall amphiphilicity and flexibility of target oligomers such as arylamides and characterized key intramolecular hydrogen bonding motifs such as N-H...S. Experimental synthesis and testing confirmed that the best compounds were membrane-active, were effective at killing a broad assortment of bacteria, and would selectively kill bacteria rather than human red blood cells. Computed hydrophobicities and hydrophobic moments showed the delicate balance required in the structure in order to give excellent antimicrobial activity and selectivity.

Novel conformationally-constrained 8-helical β-peptides

For a novel family of oxanorbornene β-peptides, a systematic multi-level computational approach including force field optimizations of all possible conformations and density functional theory computations of the three-dimensional structure and ¹H NMR chemical shifts predicts that the dimer and trimer form consecutive 8-membered hydrogen-bonded ring helices, which is supported by excellent agreement with experimental solution NMR chemical shifts and NOE-predicted distances. The role of the oxanorbornene ring in stabilizing 8-helices compared to the more commonly found 12- and other helical patterns in β-peptides is examined.

Designed intramolecular hydrogen bonds stabilizing antimicrobial amphiphilic polymers

A designed pair of intramolecular weak N-H...S hydrogen bonds provides crucial backbone rigidity for a recently reported class of amphiphilic arylamide polymer biomimetics which have shown a broad range of antimicrobial activity. Each monomer features a central 2,6-di- X, 1-Y, 4-Z-benzene unit with X = NHCO amide linker, Y = SR hydrophilic, and Z hydrophobic. The S linker in the SR side chain is intended to help prevent rotation around the ring--N bonds which would reduce the amphiphilicity of the polymer. Accurate density functional theory CCNC torsional potentials and constrained geometries demonstrate that the N-H bond stretches in a regular pattern as it is rotated to point towards S. Gas-phase Car-Parrinello dynamics and solution-phase molecular dynamics show that the NH tends to remain pointed towards S. Calculated chemical shifts and characteristic reduction in the N-H stretch frequency agree with solution-phase experimental data and further characterize the important hydrogen bonds.

Accurate energetics for in-plane versus out-of-plane phenol, thiophenol, anisole and thioanisole

There has been some controversy in experimental and theoretical work about whether the methyl substituent of thioanisole is in the phenyl plane or out of it. Also, previous work has reported that Hartree-Fock, second-order Moller-Plesset perturbation theory, density-functional theory (DFT) and hybrid DFT give qualitatively different torsional potentials for thioanisole. We calculate the in-plane and out-of-plane structures of phenol, thiophenol, anisole, and thioanisole using these methods plus the more accurate coupled cluster approach, with large basis sets including polarization and diffuse basis functions. Larger basis sets give significantly more accurate energy differences for the various methods. The most accurate estimate based on a hybrid of the best computational results shows the planar conformation to be most stable for the O-containing cases, whereas for thiophenol and thioanisole the planar and perpendicular conformations are nearly isoenergetic.

De novo design and synthesis of antimicrobial oligo-amino acid-salicylamide

De novo design of bioactive non-natural oligomers and is of both theoretical and practical importance. The resistance against enzymatic degradation and the low cost for production of biomimetic non-natural oligomers and polymers make them excellent candidates for pharmaceutical applications. Series of oligomers of hybrid amino acid-salicylamide have been designed and synthesized to mimic the overall physicochemical properties of natural antibacterial peptides such as magainin and cecropin. The design was guided by density functional calculation and molecular dynamics simulation. A library of more than 30 oligomers were synthesized to search of the leading compounds. Structure activity relationship (SAR) study was carried out. With the combination and theoretical calculation and combinatorial synthesis, highly active antibacterial oligomers with low toxicity have been achieved.

De novo design and synthesis of nonhemolytic biomimetic antimicrobial polymers

A large group of short peptides produced in eukaryotic cells act as the first line of the defence system by disrupting the bacterial cell membranes. Aided by density functional calculation, series of polymer constructed from arylamide have been designed to have facially amphiphilic structure. These polymers mimic the overall physicochemical properties of the natural antimicrobial peptides such as magainin and cecropin, show remarkable activity against a large variety of bacteria. They benefit from the low cost of production and the stability against enzymatic degradation. However, the significant ability of these polymers to lysis human erythrocytes remains a potential problem for their pharmaceutical application. In this work, modifications have been done the poly-arylamides to fine-tune their hydrophobicity/charge balance, and their toxicity has been greatly reduced while the high antimicrobial activity retained. We have thus shows a successful approach towards highly active antimicrobial polymers that have excellent selectivity.

Computational design of biomimetic materials

The design of polymers that mimic the complex structures and functions of bio-molecules is of paramount importance with both fundamental and practical implications. However, this effort is often limited by our knowledge of the microscopic-level driving forces behind certain structures and properties. Computations allow for direct probing of this information. Moreover, given a primary sequence for a polymer, they can be utilized to predict its conformational properties. This presentation will report some recent progress in using computations to guide the design of biomimetic antimicrobial material. Specifically, the conformational properties of proposed polymer backbones were examined with different levels of computational approaches before they were synthesized. First, density functional theory calculations are employed to search for stable conformations of selected polymer fragments and to determine the torsional potentials around various bonds on the polymer backbone. The torsional potentials are then applied to predict the conformational properties of the polymers using classical simulations. These calculations also yield useful insights on how various structural motifs (e.g., conjugation, hydrogen bonding, and side chain substitution) enforce desired conformation. Available experimental results show that the resulting polymers have promising antibacterial activities.

Geometries, Polarizabilities and Aromaticity of Ring Molecules

Robert J. Doerksen, Phd. Thesis
University of New Brunswick, (1998).

Ab initio, second-order, Moller-Plesset (MP2) perturbation theory calculations of the equilibrium geometries, harmonic vibrational frequencies, relative stabilities, dipole moments, and static dipole polarizabilities are reported for 87 different six pi-electron monocycles containing boron and nitrogen. These include all 17 azaborinines (commonly called azaborines) isosteric to benzene, 26 azaborinines isosteric to pyridine, 16 azaboroles, and 28 oxazaboroles.

The most stable isomers have as many as possible consecutive BHNH groups and, where applicable, contain the substructure XBHNH, where X = N, NH, or O is the base-ring heteroatom. Planar conformations are stable minima for all but 15 five-membered rings and one six-membered ring. Lower level calculations are unreliable in predicting which molecules are planar. Good agreement is found with the available electron diffraction and X-ray structures of substituted rings. The ratio of MP2 to Hartree-Fock (HF) harmonic frequencies is found to vary around an average of 0.94.

The polarizabilities, along with earlier results for the azoles, oxazoles, and azines, constitute a uniform quality data set for 120 heteroaromatic rings. Additive atom and bond polarizability models which are accurate to within a few percent are constructed for the 104 planar molecules. The presence of boron causes scatter of the polarizabilities of isomers; hence the additive models of polarizability are less accurate than if only heterocycles containing C, N, and O are included.

The relative aromaticities of azines, azoles, oxazoles, and thiazoles are analyzed using polarizabilities and bond orders. The MP2 polarizability anisotropy and the anisotropy of the pi-polarizability--calculated through a combination of uncoupled Hartree-Fock and electron correlated data--predict quite different scales of aromaticity. HF bond orders combined with the accurate MP2 geometries, an alternative to the popular Gordy bond orders derived from assorted experimental geometries, are used in order to improve previously proposed geometry-based aromaticity indexes--the Harmonic Oscillator Model of Aromaticity, Pozharskii, Ring Current, and Bird Indexes.

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