Thermoplastic polyheterocycles. I: Polyalkylene-benzoxazoles

Polyalkylenebenzoxazoles of high molecular weight (inherent viscosity values from 0.76 to 2.95) were prepared from 4,6-diaminoresorcinol dihydrochloride and aliphatic diacids in polyphosphoric acid by heating at 180 to 200°C for 3–5 h. Melting points of the polymers ranged from 148 to 423°C, depending on the length of the alkylene chain. Glass transition temperatures were relatively low, ranging from 50 to 100°C and did not show the pronounced odd/even effect noted for melting points. In all cases, rapid weight loss occurred above 400°C. No evidence for the formation of a molecular composite was observed in an attempt to prepare in situ a rod-like polybenzoxazole in a polyalkylenebenzoxazole.     

Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HTV protease

Free energy simulations (slow-change method) have been usedto estimate quantitatively the ratio of the binding constantsof (S) and (R) isomers of a novel HIV protease inhibitor, JG365.As a starting geometry, we used the X-ray crystallographic structureof a complex of HTV protease and JG365 provided by A.Wlodawer.According to our results the (S) configuration, i.e. the formpreviously identified experimentally, binds considerably moretightly to the protease (G° = 2.9 kcal/mol). When the (S)inhibitor is bound, there is a very strong preference for protonationof the Aspl25 (rather than the Asp25) residue of the protease.This study is the first to apply a new method for quantitativelyassessing the precision of free energies calculated by the slow-changemethod     

Delaunay tessellation of proteins: four body nearest-neighbor propensities of amino acid residues

Delaunay tessellation is applied for the first time in the analysis of protein structure. By representing amino acid residues in protein chains by C alpha atoms, the protein is described as a set of points in three-dimensional space. Delaunay tessellation of a protein structure generates an aggregate of space-filling irregular tetrahedra, or Delaunay simplices. The vertices of each simplex define objectively four nearest neighbor C alpha atoms, i.e., four nearest-neighbor residues. A simplex classification scheme is introduced in which simplices are divided into five classes based on the relative positions of vertex residues in protein primary sequence. Statistical analysis of the residue composition of Delaunay simplices reveals nonrandom preferences for certain quadruplets of amino acids to be clustered together. This nonrandom preference may be used to develop a four-body potential that can be used in evaluating sequence-structure compatibility for the purpose of inverted structure prediction.     

Thermoplastic polyheterocycles. II: Polyalkylene-imides

Polyalkylene-imides (i.e., aliphatic-aromatic polyimides) were prepared smoothly in N-methyl pyrollidone from straight chain aliphatic diamines and pyrromellitic dianhydride. Melting points of the polymers ranged from about 300 to 450°C, depending of the length of the alkylene chains. An odd/even effect related to the alkylene chain was noted for melting points and glass transition temperatures (T_g) of the polymers. The T_gs were relatively high, especially when compared to similarly structured polyalkylene-heterocycles, e.g., polyakylenebenzoxazoles.     

Accurate prediction of the bound conformation of galanthamine in the active site of Torpedo californica acetylcholinesterase using molecular docking.

The alkaloid (-)-galanthamine is known to produce significant improvement of cognitive performances in patients with the Alzheimer's disease. Its mechanism of action involves competitive and reversible inhibition of acetylcholinesterase (AChE). Herein, we correctly predict the orientation and conformation of the galanthamine molecule in the active site of AChE from Torpedo californica (TcAChE) using a combination of rigid docking and flexible geometry optimization with a molecular mechanics force field. The quality of the predicted model is remarkable, as indicated by the value of the RMS deviation of approximately 0.5A when compared with the crystal structure of the TcAChE-galanthamine complex. A molecular model of the complex between TcAChE and a galanthamine derivative, SPH1107, with a long chain substituent on the nitrogen has been generated as well. The side chain of this ligand is predicted to extend along the enzyme active site gorge from the anionic subsite, at the bottom, to the peripheral anionic site, at the top. The docking procedure described in this paper can be applied to produce models of ligand-receptor complexes for AChE and other macromolecular targets of drug design.