Mehran Jalaie

Model studies of six-membered water clusters

Abstract Using the molecular mechanics for clusters model, calculations have been performed that explore the types of minimum energy structures that occur for a collection of six water molecules. The results show an extensive set of structures. The global minimum structure is best described as a stack of two three-membered rings with nine close (around 3 ,) molecule-molecule separations, or “bonds”. Energetically less favorable structures occur mostly with fewer of these weak bonds; however, the energy per bond is greater in certain of the structures. In spite of the considerable variation in structures, there is a high degree of correlation between the average molecule separation distances and the stabilities for all the equilibrium structures. Furthermore, several calculations on clusters of other than six waters show the same correlation. Harmonic vibrational frequencies are presented for the most stable structures, and comparison calculations with two other widely used water potentials are reported.

Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-gamma.

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Enantiodiscrimination by a quinine-based chiral stationary phase: a computational study.

A detailed computational study of a derivatized quinine chiral stationary phase (CSP) interacting with enantiomeric 3, 5-dinitrobenzoyl derivatives of leucine was carried out to understand where and how chiral discrimination takes place. The most stable structure of the CSP derived from a conformer search gave a structure whose geometry agrees with an X-ray structure (rmsd 0.6 A). The computed retention order and enantiodiscriminating free energy differences also agree with chromatographic data. The location and characteristics of the analyte binding site were assessed. An evaluation of total energies and intermolecular energies responsible for complex formation and for chiral discrimination was performed. Molecular dynamics trajectories of those intermolecular forces as well as distributions of the stabilizing and destabilizing forces are presented. A partitioning of the CSP into molecular fragments and the role each fragment plays in complexation and chiral recognition is also described.

Comparative molecular field analysis of quinine derivatives used as chiral selectors in liquid chromatography: 3D QSAR for the purposes of molecular design of chiral stationary phases

A comparative molecular field analysis (CoMFA) was carried out on a set of aligned quinine-based stationary phase molecules used in enantioselective chromatography. The best QSAR derived has a cross-validated (predictive) r(2)(cv) = 0.671 and a normal r(2) = 0.998. For CoMFAs using both steric and electrostatic fields as descriptors, the steric field descriptors explained more than 91% of the variance while the electrostatic descriptors explained less than 9% of the variance. It is concluded that the long-range electrostatic potential surrounding the positively charged CSPs are not enantiodiscriminating, while the van der Waals and local electrostatic surface features of these CSPs are highly discriminating. Quantum mechanical calculations back up this claim by showing a relatively symmetric electrostatic iso-contour surface. From the QSAR derived here, a region around the carbamate moiety was located where placement of steric bulk is predicted to enhance chiral discrimination. A set of possible synthetic target molecules is presented.