Calculation of relative binding affinities of fructose 1,6-bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: 113Tyr --> 113Phe, 31Thr --> 31Ala, 31Thr --> 31Ser, 177Met --> 177Ala, and 30Leu --> 30Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: 113Tyr and 31Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase.     

Ab initio quantum mechanics-based free energy perturbation method for calculating relative solvation free energies

A free energy perturbation (FEP) method was developed that uses ab initio quantum mechanics (QM) for treating the solute molecules and molecular mechanics (MM) for treating the surroundings. Like our earlier results using AM1 semi empirical QMs, the ab initio QM/MM-based FEP method was shown to accurately calculate relative solvation free energies for a diverse set of small molecules that differ significantly in structure, aromaticity, hydrogen bonding potential, and electron density. Accuracy was similar to or better than conventional FEP methods. The QM/MM-based methods eliminate the need for time-consuming development of MM force field parameters, which are frequently required for drug-like molecules containing structural motifs not adequately described by MM. Future automation of the method and parallelization of the code for Linux 128/256/512 clusters is expected to enhance the speed and increase its use for drug design and lead optimization.     

Discovery of potent and specific fructose-1,6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes

Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.     

Boron 1s photoelectron spectrum of 11BF3: vibrational structure and linewidth

The boron 1s photoelectron spectrum of (11)BF(3) has been measured at a photon energy of 400 eV and a resolution of about 55 meV. The pronounced vibrational structure seen in the spectrum has been analyzed to give the harmonic and anharmonic vibrational frequencies of the symmetric stretching mode, 128.1 and 0.15 meV, as well as the change in equilibrium BF bond length upon ionization, -5.83 pm. A similar change in bond length has been observed for PF(3) and SiF(4), but a much smaller change for CF(4). Theoretical calculations for BF(3) that include the effects of electron correlation give results that are in reasonable accord with the experimental values. The Lorentzian (lifetime) width of the boron 1s core hole in BF(3) is found to be 72 meV, comparable to the value of 77 meV that has been reported for CF(4).     

BF3·Et2O promoted selective synthesis of benzimidazoles

Benzimidazoles 3 , 6 and 9 have been synthesized selectively in excellent yields by cyclocondensation of β‐(3‐methyl‐5‐styryl‐4‐isoxazolyl amido) benzoic acids, acrylic acids and propionic acids with 1,2‐phenylene diamines by employing BF₃·Et₂O as the catalyst. When the same reaction was carried out in pyridine it resulted in mixture of products in each case ( 3 & 4 , 6 & 7 and 9 & 10 ). Other methods tried by using polyphosphoric acid, HCl, TFA also led to mixtures of 3 & 4 , 6 & 7 and 9 & 10 in each case, similar to that of pyridine reaction.     

Solvation free energies calculated using the GB/SA model: Sensitivity of results on charge sets,protocols, and force fields

The sensitivity of aqueous solvation free energies (SFEs), estimated using the GB/SA continuum solvent model, on charge sets, protocols, and force fields, was studied. Simple energy calculations using the GB/SA solvent model were performed on 11 monofunctional organic compounds. Results indicate that calculated SFEs are strongly dependent on the charge sets. Charges derived from electrostatic potential fitting to high level ab initio wave functions using the CHELPG procedure and “class IV” charges from AM1/CM1a or PM3/CM1p calculations yielded better results than the corresponding Mulliken charges. Calculated SFEs were similar to MC/FEP energies obtained in the presence of explicit TIP4P water. Further improvements were obtained by using GVB/6-31G** and MP2/6-31+G** (CHELPG) charge sets that included correlation effects. SFEs calculated using charge sets assigned by the OPLSA* force field gave the best results of all standard force fields (MM2*, MM3*, MMFF, AMBER*, and OPLSA*) implemented in MacroModel. Comparison of relative and absolute SFEs computed using either the GB/SA continuum model or MC/FEP calculations in the presence of explicit TIP4P water showed that, in general, relative SFEs can be estimated with greater accuracy. A second set of 20 mono- and difunctional molecules was also studied and relative SFEs estimated using energy minimization and thermodynamic cycle perturbation (TCP) protocols. SFEs calculated from TCP calculations using the GB/SA model were sensitive to bond lengths of dummy bonds (i.e., bonds involving dummy atoms). In such cases, keeping the bond lengths of dummy bonds close to the corresponding bond lengths of the starting structures improved the agreement of TCP-calculated SFEs with energy minimization results. Overall, these results indicate that GB/SA solvation free energy estimates from simple energy minimization calculations are of similar accuracy and value to those obtained using more elaborate TCP protocols. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 769–780, 1998     

Scalar Tensor Cosmology With Kinetic,Gauss-Bonnet and Nonminimal Derivative Couplings and Supersymmetric Loop Corrected Potential

We discuss a particular four-dimensional cosmology based on non-minimal scalar tensor theories characterized by a supersymmetric loop corrected potential and a Hubble parameter defined as a function of the scalar field. Power-law solutions are obtained in the FRW background giving rise to acceleratedly expanding universe characterized by a scale factor and a scalar field depending both on the non-minimal coupling parameter $\xi$. Based on SNeIa data and on Hubble data X-ray gas mass fraction measurements, we find $0.116<\xi <0.225$ which results on a universe dominated by vacuum energy.     

Nonlocal approach to nonequilibrium thermodynamics and nonlocal heat diffusion processes

We study some aspects of nonequilibrium thermodynamics and heat diffusion processes based on Suykens’s nonlocal-in-time kinetic energy approach recently introduced in the literature. A number of properties and insights are obtained in particular the emergence of oscillating entropy and nonlocal diffusion equations which are relevant to a number of physical and engineering problems. Several features are obtained and discussed in details.     

Nanoplasmonic directional couplers and Mach–Zehnder interferometers

We present a novel design and analysis of two nano-scale plasmonic devices: a directional coupler and a Mach–Zehnder interferometer. The designs of the two devices are based on our recent work on the air-gap coupler that resulted in high coupling efficiency between a dielectric waveguide and a plasmonic waveguide. The two devices are embedded between two dielectric waveguides and operate at optical telecom wavelengths. The overall efficiency was 37% for a 2×2 directional coupler switch and above 50% for the proposed designs for a Mach–Zehnder Interferometer. The efficiency in the proposed devices can be increased using broader plasmonic waveguides.     

Fractional dynamics, fractional weak bosons masses and physics beyond the standard model

I discuss the possibility of manifestation of the ultralight Hubble mass in the Affleck–Dine mechanism and the time-variation of the gauge-coupling constant beyond the standard electroweak model. Exceedingly small correction to the standard theory in terms of “fractional weak boson mass” of the same order of magnitude the mass uncertainties found in the Particle Data Group tables is obtained and thus related to the space-time fractionality. The mathematics is based on fractional action-like variational problems recently introduced by the author that generalize the d’Alembertian operator of conventional quantum field theory.