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651.
Sarah L. Kidd Elaine Fowler Till Reinhardt Thomas Compton Natalia Mateu Hector Newman Dom Bellini Romain Talon Joseph McLoughlin Tobias Krojer Anthony Aimon Anthony Bradley Michael Fairhead Paul Brear Laura Díaz-Sez Katherine McAuley Hannah F. Sore Andrew Madin Daniel H. O'Donovan Kilian V. M. Huber Marko Hyvnen Frank von Delft Christopher G. Dowson David R. Spring 《Chemical science》2020,11(39):10792
Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.Fragment-based screening of a shape-diverse collection yielded four hits against three proteins. Up to 14 analogues of each hit were rapidly generated, enabling four fragment growth vectors to be explored using inexpensive materials and reliable synthetic transformations. 相似文献
652.
Tommaso Bellini Vittorio Degiorgio Francesco Mantegazza 《Colloids and surfaces. A, Physicochemical and engineering aspects》1998,140(1-3):103-117
We discuss the Kerr constant of a polyelectrolyte solution in the dilute regime. We show that the birefringence induced in a suspension of nonspherical polyelectrolytes by an external electric field probes the electrokinetic properties of the suspension. This is because the Kerr constant is directly connected to the electric torque exerted on the particles, and therefore contains information on the induced dipole, similarly to the other electrokinetic techniques. The article is a guideline for the development of an electrokinetic theory of the electric birefringence of polyelectrolytes. We compare two different methods to derive the Kerr constant of the polyelectrolyte solution. The first method uses an expression for the electric torque which is obtained through electrostatics, and yields a Kerr constant which has the same frequency dependence as the anisotropy of the real part of the polarizability of the dressed particle (that is, of the particle plus surrounding ions). The second method assigns an effective value of the induced electric dipole per particle by using the theory of the dielectric enhancement, and gives a Kerr constant proportional to the anisotropy of the real part of the dielectric constant of the suspension. The two methods give a considerably different frequency dependence of the Kerr constant: we suggest that the expression obtained by the second method is more capable of correctly describing the main features of the experimental results obtained with polyelectrolytes having small shape anisotropy. 相似文献
653.
Kochendoerfer GG Jones DH Lee S Oblatt-Montal M Opella SJ Montal M 《Journal of the American Chemical Society》2004,126(8):2439-2446
Vpu is an 81-residue integral membrane protein encoded in the HIV-1 genome that is of considerable interest because it plays important roles in the release of virus particles from infected cells and in the degradation of the cellular receptor. We report here the total chemical synthesis of full-length Vpu(1-81) as well as a site-specifically (15)N-labeled analogue, Vpu(2-81), using native chemical ligation methodologies and also report a structural and functional comparison of these constructs with recombinant protein obtained via bacterial expression. The structures of the synthetic and expressed polypeptides were similar in lipid micelles using solution NMR spectroscopy. Solid-state NMR spectra of the polypeptides in aligned hydrated lipid bilayers indicated that their overall topologies were also very comparable. Further, the channel activity of the synthetic protein was found to be analogous to that previously characterized for the recombinant protein. We have thus demonstrated that using solid phase peptide synthesis and chemical ligation it is feasible to obtain large quantities of a purified and homogeneous membrane protein in a structurally and functionally relevant form for future structural and characterization studies. 相似文献
654.
A. Hardisson R. Lefebvre F. Mauricio S. Velasco 《International journal of quantum chemistry》1977,11(2):301-315
This paper studies the decay, due to the spin-lattice coupling, of two ½ spins with slightly different Zeeman energies when the lattice is thermally excited. The analysis is based on obtaining, by means of the Nakajima–Zwanzig projection operator technique, an equation for the evolution of the reduced density operator of the spin system which manifests the influence of one spin on the relaxation process of the other. The zero-order solutions obtained for the evolution of the expectation values of the spin dynamics operators are essentially equivalent to the Bloch equations; higher order solutions are also obtained. 相似文献
655.
Carlos Mauricio R. de Sant'Anna Ricardo Bicca de Alencastro Eliezer J. Barreiro Carlos A. M. Fraga 《Journal of Molecular Structure》1995,340(1-3):193-199
The stereoselective mechanism of reduction of 2-methoxycarbonyl-2-allyl-cyclopentanone with BH4− was investigated with the AM1 method in the gas phase. Geometries of reactants, transition states, and products were obtained for the reactions conducting to both trans and cis alkoxides. The results suggest that the stereoselectivity is of steric origin. The effect of a chelating Zn2+ ion on the reaction stereoselectivity was analyzed. 相似文献
656.
Anil P. Kamath Narendra K. Karmarkar K. G. Ramakrishnan Mauricio G. C. Resende 《Mathematical Programming》1992,57(1-3):215-238
In this paper we describe an interior point mathematical programming approach to inductive inference. We list several versions of this problem and study in detail the formulation based on hidden Boolean logic. We consider the problem of identifying a hidden Boolean function:{0, 1}
n
{0, 1} using outputs obtained by applying a limited number of random inputs to the hidden function. Given this input—output sample, we give a method to synthesize a Boolean function that describes the sample. We pose the Boolean Function Synthesis Problem as a particular type of Satisfiability Problem. The Satisfiability Problem is translated into an integer programming feasibility problem, that is solved with an interior point algorithm for integer programming. A similar integer programming implementation has been used in a previous study to solve randomly generated instances of the Satisfiability Problem. In this paper we introduce a new variant of this algorithm, where the Riemannian metric used for defining the search region is dynamically modified. Computational results on 8-, 16- and 32-input, 1-output functions are presented. Our implementation successfully identified the majority of hidden functions in the experiment. 相似文献
657.
658.
Karina Van Sickle Lori Marie Culberson Jeremy Levin Holzmacher Mauricio Cafiero 《International journal of quantum chemistry》2007,107(6):1523-1531
In an effort to evaluate and design fast, accurate density functional theory (DFT) methods for calculating electrostatic and dispersion interactions between proteins and ligands, we have set up a model system examining interactions between mono‐substituted benzene and indole in seven different stable conformations. We first optimized the geometries of the monomers at the B3LYP/6‐31G level, and then scanned the potential curves with MP2, HF, B3LYP, SVWN, and HCTH407 [all at the 6‐311++G(d,p) level] to find the optimum separation. We used the approximate counterpoise method to calculate the basis set superposition error‐corrected interaction energies at the optimum geometries. We then applied these methods to the interactions between aromatic active site residues of horseradish peroxidase C with indole‐3‐propionic acid at two different binding sites. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 相似文献
659.
Cabeza M Flores E Heuze I Sánchez M Bratoeff E Ramírez E Francolugo VA 《Chemical & pharmaceutical bulletin》2004,52(5):535-539
The in vitro antiandrogenic activity of four new progesterone derivatives: 4, 5, 6 and 7 (8 is a known compound) was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as by their capacity to bind to the androgen receptor in gonadectomized hamster prostate. The IC(50) value was determined using increasing concentrations of 4, 5, 6, 7 and 8 in the presence of [(3)H]T and the microsomal fraction of the hamster prostate containing the 5alpha-reductase enzyme. In this paper we also demonstrated the effect of increasing concentrations of the novel steroids upon [(3)H]DHT binding to the androgen receptors from hamster prostate which produces competition for the androgen receptor sites. The in vitro studies showed that steroids 4, 5, 6, 7 and 8 had an inhibitory activity for the 5alpha-reductase with IC(50) of: 4 (0.17 microM), 5 (0.19 microM), 6 (1 microM), 7 (4.2 microM), and 8 (2.7 microM). On the other hand, the IC(50) value for compounds 4, 5, 6, 7, 8 and DHT showed the following order of affinity for the androgen receptor: 6>7>5>DHT. Surprisingly compounds 4 and 8 did not bind to the androgen receptor. The overall data indicate that all synthesized compounds are inhibitors for the enzyme 5alpha-reductase present in the hamster prostate. In contrast, compounds 5, 6 and 7, which have a cyclohexyl group in the side chain showed a high affinity for the androgen receptor. 相似文献
660.
Erben MF Della Védova CO Boese R Willner H Leibold C Oberhammer H 《Inorganic chemistry》2003,42(22):7297-7303
The geometric structure and conformational properties of trifluoromethyl chlorosulfonate (chlorosulfuric acid trifluoromethyl ester), CF(3)OSO(2)Cl, have been determined by X-ray crystallography, gas electron diffraction (GED), and vibrational spectroscopy (IR(gas), IR(matrix), and Raman(liquid)). These experimental investigations were supplemented by quantum chemical calculations (B3LYP with 6-311G* and 6-311+G(3df) basis sets). All experimental methods result in a single conformer with gauche orientation of the CF(3) group relative to the S[bond]Cl. The dihedral angle delta(COSCl) is determined to be 91.7(3) degrees in the crystal and 94(3) degrees in the gas phase. This dihedral angle corresponds to a near-eclipsed orientation of the O[bond]C relative to one of the S[double bond]O bonds (delta(CO[bond]SO) = -23.0(3) degrees and -21(3) degrees in the crystal and gas phase, respectively). 相似文献