Optimization of diarylazines as anti-HIV agents with dramatically

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Scaling by 5 on a 1/4-Cantor Measure

Each Cantor measure (\mu) with scaling factor 1/(2n) has at least one associated orthonormal basis of exponential functions (ONB) for L^2(\mu). In the particular case where the scaling constant for the Cantor measure is 1/4 and two specific ONBs are selected for L^2(\mu), there is a unitary operator U defined by mapping one ONB to the other. This paper focuses on the case in which one ONB (\Gamma) is the original Jorgensen-Pedersen ONB for the Cantor measure (\mu) and the other ONB is is 5\Gamma. The main theorem of the paper states that the corresponding operator U is ergodic in the sense that only the constant functions are fixed by U.Comment: 34 page

PDDG/PM3 and PDDG/MNDO: improved semiempirical methods

Two new semiempirical methods employing a Pairwise Distance Directed Gaussian modification have been developed: PDDG/PM3 and PDDG/MNDO; they are easily implemented in existing software, and yield heats of formation for compounds containing C, H, N, and O atoms with significantly improved accuracy over the standard NDDO schemes, PM5, PM3, AM1, and MNDO. The PDDG/PM3 results for heats of formation also show substantial improvement over density functional theory with large basis sets. The PDDG modifications consist of a single function, which is added to the existing pairwise core repulsion functions within PM3 and MNDO, a reparameterized semiempirical parameter set, and modified computation of the energy of formation of a gaseous atom. The PDDG addition introduces functional group information via pairwise atomic interactions using only atom-based parameters. For 622 diverse molecules containing C, H, N, and O atoms, mean absolute errors in calculated heats of formation are reduced from 4.4 to 3.2 kcal/mol and from 8.4 to 5.2 kcal/mol using the PDDG modified versions of PM3 and MNDO over the standard versions, respectively. Several specific problems are overcome, including the relative stability of hydrocarbon isomers, and energetics of small rings and molecules containing multiple heteroatoms. The internal consistency of PDDG energies is also significantly improved, enabling more reliable analysis of isomerization energies and trends across series of molecules; PDDG isomerization energies show significant improvement over B3LYP/6-31G∗ results. Comparison of heats of formation, ionization potentials, dipole moments, isomer, and conformer energetics, intermolecular interaction energies, activation energies, and molecular geometries from the PDDG techniques is made to experimental data and values from other semiempirical and ab initio methods

The Distance to the Coma Cluster from Surface Brightness Fluctuations

We report on the first determination of the distance to the Coma Cluster based on surface brightness fluctuation (SBF) measurements obtained from Hubble Space Telescope WFPC2 observations of the bright E0 galaxy NGC 4881 in the Coma Cluster and ground-based observations of the standard E1 galaxy NGC 3379 in the Leo-I group. Relative distances based on the I-band fluctuation magnitude, I(SBF), are strongly dependent on metallicity and age of the stellar population. However, the radial changes in the stellar populations of the two giant ellipticals, NGC 3379 and NGC 4881, are well described by published Mg_2 gradients, and the ground-based measurements of I(SBF) at several radial points in NGC 3379 are used to calibrate I(SBF) in terms of the Mg_2 index. The distance to NGC 3379, assumed to be identical to the average SBF distance of the Leo-I group, is combined with the new SBF measurements of NGC 4881 to obtain a Coma Cluster distance of 102+-14 Mpc. Combining this distance with the cosmic recession velocity of Coma (7186+-428 km/s), we find the Hubble constant to be H_0 = 71+-11 km/s/Mpc.Comment: 12 pages, LaTex, includes aaspp4.sty and 3 eps figures. To appear in ApJ Letter

Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase

Using a computationally driven approach, a class of inhibitors with picomolar potency known as the catechol diethers were developed targeting the non-nucleoside-binding pocket of HIV-1 reverse transcriptase. Computational studies suggested that halogen-bonding interactions between the C5 substituent of the inhibitor and backbone carbonyl of conserved residue Pro95 might be important. While the recently reported crystal structures of the reverse transcriptase complexes confirmed the interactions with the non-nucleoside-binding pocket, they revealed the lack of a halogen-bonding interaction with Pro95. To understand the effects of substituents at the C5 position, we determined additional crystal structures with 5-Br and 5-H derivatives. Using comparative structural analysis, we identified several conformations of the ethoxy uracil dependent on the strength of a van der Waals interaction with the Cγ of Pro95 and the C5 substitution. The 5-Cl and 5-F derivatives position the ethoxy uracil to make more hydrogen bonds, whereas the larger 5-Br and smaller 5-H position the ethoxy uracil to make fewer hydrogen bonds. EC50 values correlate with the trends observed in the crystal structures. The influence of C5 substitutions on the ethoxy uracil conformation may have strategic value, as future derivatives can possibly be modulated to gain additional hydrogen-bonding interactions with resistant variants of reverse transcriptase.Fil: Frey, Kathleen M.. University of Yale; Estados UnidosFil: Gray, William T.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale; Estados UnidosFil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallardo Macias, Ricardo. University of Yale; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados UnidosFil: Anderson, Karen S.. University of Yale; Estados Unido

Influence of Cooled Interstellar Gas on the Fundamental Plane for Elliptical Galaxies

We explore the possibly important influence of cooled interstellar gas on the fundamental plane of elliptical galaxies. Interstellar cooling is described by a parameterized sink term in the equation of continuity. Parameters that give the best fits to the X-ray observations of NGC 4472 are used as a template for the radial distribution of interstellar cooling in structurally homologous elliptical galaxies of lower mass. Gas that cools within an effective radius can contribute an additional 10 - 30 percent to the mass of the old stellar population. If the cooled gas forms into stars of very low mass, $\ll M_{\odot}$, as is commonly assumed, the cooled mass is optically dark. As a result, the mass to light ratios determined from stellar velocities systematically overestimate that of the old stellar population. Moreover, the total mass and spatial distribution of the optically dark young stellar population does not scale homologously with galactic luminosity or radius and the total stellar mass to light ratio varies with galactic radius. We investigate the non-homologous perturbations of cooled gas on the mass to light ratio for several idealized homologous elliptical galaxies and show that they appear to be incompatible with the observed thinness of the fundamental plane. If optically luminous young stars formed from the cooled gas, the disturbance of the fundamental plane would be lessened.Comment: 10 pages with 2 figures; accepted by Astrophysical Journa

Prediction of the Water Content in Protein Binding Sites

An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein-ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as JAWS, features “θ-water” molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more efficient than conventional free energy simulations. Testing of JAWS on five diverse examples (neuraminidase, scytalone dehydratase, major urinary protein 1, β-lactoglobulin, and COX-2) demonstrates its accuracy in locating hydration sites in comparison to results from high-resolution crystal structures. Possible applications include aid in refinement of protein crystal structures, drug lead optimization, setup of docking calculations and simulations of protein-ligand complexes

Conformational Complexity of Succinic Acid and Its Monoanion in the Gas Phase and in Solution: Ab Initio Calculations and Monte Carlo Simulations

Optimized structures and relative energies for conformers of succinic acid and its monoanion in the gas phase were obtained using ab initio molecular orbital calculations at the MP2/6-311+G^(**)//HF/6-31G^* and MP2/6-311+G^(**)//HF/6-31+G^* levels, respectively. The lowest energy conformer for succinic acid, designated ZsgsZ, has a gauche conformation about the central C2−C3 bond; the lowest energy conformer with an E-acid group and an internal hydrogen bond is ca. 3 kcal/mol higher in energy. The lowest energy structure for the monoanion, Ecgs, does have the expected internal hydrogen bond and is 15 kcal/mol more stable than any alternative. The ab initio results were used to determine corresponding torsional-energy parameters in the OPLS all-atom force field. This allowed application of statistical perturbation theory in Monte Carlo simulations to explore the effect of hydration on the conformational equilibria. The diacid and monoanion were both computed to be ca. 80% gauche in water at 25 °C. These results are in excellent agreement with NMR data. Though the conformational results are consistent with the gauche effect, their true origin requires a detailed understanding of the potential internal hydrogen bonding and solvation. Thus, in contrast to the monoanion's striking gas-phase preference, neither the diacid nor monoanion are computed to populate E conformers in aqueous solution

Absolute Free Energy of Binding Calculations for Macrophage Migration Inhibitory Factor in Complex with a Druglike Inhibitor

Calculation of the absolute free energy of binding (ΔGbind) for a complex in solution is challenging owing to the need for adequate configurational sampling and an accurate energetic description, typically with a force field (FF). In this study, Monte Carlo (MC) simulations with improved side-chain and backbone sampling are used to assess ΔGbind for the complex of a druglike inhibitor (MIF180) with the protein macrophage migration inhibitory factor (MIF) using free energy perturbation (FEP) calculations. For comparison, molecular dynamics (MD) simulations were employed as an alternative sampling method for the same system. With the OPLS-AA/M FF and CM5 atomic charges for the inhibitor, the ΔGbind results from the MC/FEP and MD/FEP simulations, −8.80 ± 0.74 and −8.46 ± 0.85 kcal/mol, agree well with each other and with the experimental value of −8.98 ± 0.28 kcal/mol. The convergence of the results and analysis of the trajectories indicate that sufficient sampling was achieved for both approaches. Repeating the MD/FEP calculations using current versions of the CHARMM and AMBER FFs led to a 6 kcal/mol range of computed ΔGbind. These results show that calculation of accurate ΔGbind for large ligands is both feasible and numerically equivalent, within error limits, using either methodology