Tapan K. Chattopadhyay

3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists

The integrin VLA-4 (α4β1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CVof 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.

Molecular and absolute crystal structure of pindolol-1-(1H-indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol: A specific beta-adrenoreceptor antagonist with partial agonist activity

AbstractThe crystal and molecular structure of pindolol, 1-(1H indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol, has been determined by direct methods. Crystals are tetragonal,

Gold(III) and palladium(II) complexes ofglycylglycyl-L-histidine: crystal structures of[AuIII(Gly-Gly-L-His-H-2)]Cl·H2O and[PdII(Gly-Gly-L-His-H-2)]·1.5H2O and HisεNH deprotonation

P\bar 42_1 c

X-ray structural and potential energy studies on zentropil (5,5-diphenyl-2,4-imidazolidine dione)

,a=b=15.809(4),c=11.246(2) Å,Z=8,Dc=1.174 mg m−3. The finalR-factor for 2271 reflections withI>2σ(I) is 0.038. Refinement by full-matrix least-squares on F2 also enabled the absolute configuration of the structure to be established. The molecule is essentially planar, including much of the side-chain which is stabilized by the existence of two intramolecular H-bonds, between the ethyl oxygen and OH group, and between the OH and side-chain amide groups, respectively. The crystal structure is formed by three intermolecular hydrogen bonds including two side-chain-side-chain interactions, between ethyl oxygen to amide and OH to amide, and an interaction between the side-chain OH to indole NH.

X-Ray Crystal Structure and Solution Properties of [Au(III)(H-2-Gly-Gly-L-His)]Cl.H2O

Crystals of Pleurotus ostreatus (oyster mushroom) lectin have been grown by the hanging-drop technique using ammonium sulfate as the precipitant at 293 K. Over a period of between two and three weeks, crystals of hexagonal bipyramidal morphology grew to maximum dimensions of 0.2 x 0.2 x 0.5 mm. The crystals belong to space group P6(1)22 or P6(5)22, with unit-cell parameters a = b = 155.9, c = 149. 8 A, V = 3153078 A(3), Z = 12 (assuming 50% solvent), and diffract to 4.1 A at 293 K.

Crystal structure of 20ζ-hydroxy-3β-pyrrolidino-5-pregnene-16α-carbonitrile (HS1175): A novel design for neuromuscular blocking drugs

Proton NMR studies show that [AuCl 4 ] - reacts slowly with glycylglycyl-L-histidine (Gly-Gly-L-His) (t ½ = 9.3 h at 310 K and pH* 2) in D 2 O at pH* (meter reading) values as low as 1.5 to form the stable complex [Au III (Gly-Gly-L-His-H -2 )]Cl ·H 2 O 1 via one intermediate. Complex 1 is shown by X-ray crystallography to be square-planar with gold bound to the terminal NH 2 [Au–N 2.049(10) A], two deprotonated amide nitrogens [Au–N - 1.941(9), 2.006(10) A] and HisδN [Au–N 2.038(9) A] giving one six-membered and two five-membered chelate rings. At pH* 7 the reaction of [AuCl 4 ] - with Gly-Gly-L-His follows a different course, apparently involving the formation of Au III cross-linked polymers. The anion [PdCl 4 ] 2- reacts rapidly with Gly-Gly-L-His also at pH* 2, and forms a similar square-planar complex [Pd II (Gly-Gly-L-His-H -2 )] ·1.5H 2 O 2 involving the terminal NH 2 [Pd–N 2.058(7) A], two deprotonated amide nitrogens [Pd–N - 1.943(7), 1.983(6) A] and HisδN [Pd–N 2.016(6) A]. By potentiometry, pK a values of 2.58 (CO 2 H), 8.63 (HiseNH, ‘pyrrole nitrogen’) and 11.50 (co-ordinated NH 2 ) for 1 and 11.30 (HiseNH) for 2 were determined and confirmed by 1 H NMR spectroscopy.

Structure, absolute configuration, and conformation of a fused complex cyclic carbohydrate from a cameroon plant extract (CAMT2)

ABri is a 34 residue polypeptide that forms amyloid fibrils in Familial British Dementia (FBD). A PSI-Blast search, 3 different fold recognition programs and 3D model-building indicated that it has 3 beta-strands forming an antiparallel beta-sheet and a small C-terminal alpha-helix. In order to validate the prediction, the region coding the ABri polypeptide was cloned, expressed and purified from E. Coli. Circular Dichroism (CD) spectroscopy of ABri in aqueous solution shows it to have a predominantly beta-sheet structure with a small alpha-helical component.

Crystal and molecular structure of 4,17a-methy1-4, 17a-diaza-5α-androstane (HS353): An intermediate in the design of azasteroid neuromuscular blocking agents

The structure of the title compound has been determined by direct methods from diffractometer data and refined by full-matrix least squares. Crystals are orthorhombicPn21a,a=6.228(1),b=13.568(1),c=15.520(2)Å,Z=4,Dx=1.34 g cm−3,R=0.072 for 1,152 observed reflections. The plane of the imidazolidinedione ring forms angles of 113.9° and 114.1° with the planes through the two phenyl rings. The phenyl-phenyl angle is 89.1°. Intermolecular hydrogen-bonding occurs between the oxygen and nitrogen atoms of the imidazolidinedione moiety.