Computational chemistry in drug lead discovery and design

The main contributions of our group during the last 15 years developing and using biomolecular simulation tools in drug lead discovery and design, in close collaboration with experimental researchers, are presented. Special emphasis has been given to methodological improvements in the following areas: (1) target homology modeling incorporating knowledge about known ligands to accurately characterize the binding site; (2) designing alternative strategies to account for protein flexibility in high-throughput docking; (3) development of stochastic- and normal-mode-based methods to de novo design structurally diverse protein conformers; (4) development and validation of quantum mechanical semi-empirical linear-scaling calculations to correctly estimate ligand binding free energy. Several successful cases of computer-aided drug discovery are also presented, especially our recent work on viral targets.     

Enantioselective metal-free reduction of ketones by a user-friendly silane with a reusable chiral additive

1-Hydrosilatrane, a safe and easy-to-handle reducing reagent that can be inexpensively accessed, has been shown to reduce prochiral ketones asymmetrically in the presence of chiral 1,2-aminoalcohols with ees ranging from 8% to 86%. The best result was achieved using ephedrine as the source of chirality, which is readily commercially available. The additive can be recovered through extraction and reused without any erosion of enantioselectivity.     

Defects and microvoids in a-Si and a-Si:H

We report the first measurements of positron-annihilation spectra of samples of both pure and hydrogenated amorphous silicon. Comparison of these spectra with that of crystalline silicon indicates that the lowest-lifetime component can be identified as the contribution mainly from valence-band electrons. Both the pure (a-Si) and the hydrogenated (a-Si:H) samples exhibit a component with intermediate lifetime, which we attribute to small vacancies consisting of about 4 missing atoms. Finally, only a-Si:H shows a significant long-lived line (τ > 5 ns), which arises from large microvoids, with ～ 100 missing atoms. The existence of these microvoids in a-Si:H is consistent with recent reports of the presence of occluded H₂ gas under high pressure in such films.     

Electrical conduction mechanisms in amorphous GeTe thin films

A measurement of potential distribution was carried out on amorphous GeTe thin films at various applied voltages. The potential falls steeply near the anode. The results were consistently explained with the hypothesis that the free carriers which flow away from the regions near the cathode and the anode into the inner part of the sample are not replenished by injected carriers. An estimate was made of the density of space-charge and of the free carrier concentration as a function of position. The fact that the distributions of both the potential and the free carrier concentration are nonuniform indicate that the diffusion current cannot be neglected. In the steady state, the observed current density as a function of applied field agrees well with the predictions of a theoretical model that includes both diffusion and drift currents.     

Universal electro-osmosis formulae for porous media

Approximate analytical formulae valid for any porous media with elongated pores are derived for the electro-osmotic coefficient alpha and for the average ionic concentration n . A macroscopic Debye-Hückel length kappa (-)(-1) based on n is introduced. Simultaneously, the electro-osmotic coefficient alpha is systematically calculated for various media, zeta potentials and electrolyte concentrations by solving the local equations. Numerical results show that kappa (-)(-1) and alpha follow universal curves valid whatever the porous medium; these curves can be approximated by the analytical formulae previously derived. These formulae can be used to provide a priori estimates of the electro-osmotic coefficient.     

Phytotoxicity assessment of diclofenac and its phototransformation products

The occurrence of pharmaceuticals in the environment is an emerging issue. Several studies observed that the non-steroidal anti-inflammatory drug diclofenac is ubiquitously present in most of the surveyed surface waters, worldwide. Phototransformation of diclofenac was reported from laboratory assays as well as in natural water systems, raising the question of possible adverse effects of the phototransformation products of diclofenac to aquatic organisms. In this study the phytotoxicity of diclofenac exposed to natural sunlight was evaluated using synchronized cultures of the unicellular chlorophyte Scenedesmus vacuolatus. Diclofenac dissolved in ultra-pure water at 50 mg L⁻¹ was exposed to natural midsummer sunlight for a maximum of 145 h. Twice a day subsamples were taken for chromatography and parallel phytotoxicity assessment. Inhibition of algal reproduction of the initial diclofenac solution was in the mg L⁻¹ range indicating no specific toxicity of diclofenac towards S. vacuolatus. Fast degradation of diclofenac was observed with half lives between 3.3 and 6.4 h during the first and the third day of exposure, respectively. Phytotoxicity increased after 3.5 h of exposure of diclofenac to sunlight and showed a maximum of sixfold enhanced toxicity after 53 h of exposure to sunlight. Several phototransformation products were found during the experiment. The time courses of the relative concentration of three transformation products significantly correlated with enhanced phytotoxicity during the experiment. This indicates a high toxicity potential of phototransformation products of diclofenac at concentration levels that may come close to environmental concentrations of residual diclofenac after degradation. We conclude that toxicity assessment of phototransformation products should be included in the risk assessment of pharmaceuticals in the environment.     

A simple and efficient CCSD(T)-F12 approximation

A new explicitly correlated CCSD(T)-F12 approximation is presented and tested for 23 molecules and 15 chemical reactions. The F12 correction strongly improves the basis set convergence of correlation and reaction energies. Errors of the Hartree-Fock contributions are effectively removed by including MP2 single excitations into the auxiliary basis set. Using aug-cc-pVTZ basis sets the CCSD(T)-F12 calculations are more accurate and two orders of magnitude faster than standard CCSD(T)/aug-cc-pV5Z calculations.     

One-dimensional SAMs of (12-pyrrol-1-yl-dodecyl)-phosphonic acid templated by polyelectrolyte molecules

We present a novel method for the fabrication of one-dimensional (1-D) self-assembled monolayers and multilayers (SAMs) of (12-pyrrol-1-yl-dodecyl)-phosphonic acid (Py-DPA) on various polar surfaces using polyelectrolyte nanostructures as positive templates. Particularly, we demonstrate that (i) patterns of aligned 1-D polycation structures on a poly(dimethylsiloxane) stamp can be prepared by moving a droplet of polycation solution along the surface; (ii) these patterns can be used as templates for the ordered assembly of Py-DPA in water where Py-DPA carries a charge opposite to the charge of the template; and (iii) Py-DPA SAMs can then be transferred onto mica or silicon wafers by a printing process. These nanostructures with a polymerizable pyrrole headgroup might be useful for the creation of electrically conductive patterns of conjugated polymers.