Drug Design and Discovery 

About: Drug Design and Discovery is an academic journal. The journal publishes majorly in the area(s): Binding site & Ligand (biochemistry). It has an ISSN identifier of 1026-7921. Over the lifetime, 229 publications have been published receiving 2916 citations.

Development of a comprehensive pharmacophore model for the benzodiazepine receptor.

Abstract: A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the techniques of chemical synthesis, radioligand binding, and receptor mapping. This model is based on 136 different ligands spanning ten structurally diverse classes of compounds and qualitatively accounts for the relative affinities, efficacies, and functional effects (agonism vs. antagonism vs. inverse agonism) displayed by various ligands at the BzR. In addition, the model is expanded to account for the pharmacology of a recently discovered BzR receptor subtype termed the 'Diazepam-Insensitive' (DI) BzR. Moreover, the unified model described here is compared and contrasted with other published pharmacophore models. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model. Partial agonists are of interest as potentially improved agents for treatment of anxiety disorders, while the partial inverse agonists may furnish important clues for the treatment of age-associated memory impairment.

QSAR, diagnostic statistics and molecular modelling of 1,4-dihydropyridine calcium antagonists: a difficult road ahead.

Abstract: Quantitative structure-activity relationships of a series of substituted 1,4-dihydropyridine calcium channel antagonists were studied. The analysis is difficult because of the problem of multicollinearity of substituent parameters, a high-leverage point, and position-dependent grouped observations. Canonical regression appears to be the method of choice. With respect to a maximum activity, it was shown that the following rank order of substituent parameters exists: Lipophilicity approximately ortho-position > inductivity > minimum width > meta-position. The molecular conformation of antagonists does not differ markedly (with exception of nifedipine derivatives and nimodipine), but differences seem to exist between the antagonists and the activator BAY K 8644.

Modelling the P2Y purinoceptor using rhodopsin as template.

Abstract: The P2Y1 purinoceptor cloned from chick brain (Webb, T. et al (1993) FEBS Lett., 324, 219-225) is a 362 amino acid, 41 kDa protein. To locate residues tentatively involved in ligand recognition a molecular model of the P2Y purinoceptor has been constructed. The model was based on the primary sequence and structural homology with the G-protein coupled photoreceptor rhodopsin, in analogy to the method proposed by Ballesteros and Weinstein ((1995) Meth. Neurosci. 25, 366-428). Transmembrane helices were constructed from the amino acid sequence, minimized individually, and positioned in a helical bundle. The helical bundle was then minimized using the Amber forcefield in Discover (BIOSYM Technologies) to obtain the final model. Several residues that have been shown to be critical in ligand binding in other GPCRs are conserved in the P2Y1 purinoceptor. According to our model the side chains of these conserved residues are facing the internal cleft in which ligand binding likely occurs. The model also suggests four basic residues (H121 in TM3, H266 and K269 in TM6 and R299 in TM7) near the extracellular surface that might be involved in ligand binding. These basic residues might be essential in coordinating the triphosphate chain of the endogenous ligand adenosine 5'-triphosphate (ATP). Potential binding sites for agonists have been explored by docking several derivatives (including newly synthesized N6-derivatives) into the model. The N6-phenylethyl substituent is tolerated pharmacologically, and in our model this substituent occupies a region predominantly defined by aromatic residues such as F51 (TM1), Y100 (TM2) and F120 (TM3). The dimethylated analogue of ATP, N6,N6-dimethyl-adenosine 5'-triphosphate, is less well tolerated pharmacologically, and our model predicts that the attenuated activity is due to interference with hydrogen bonding capacity to Q296 (TM7).

Synthesis and antitumor activity of poly(ethylene glycol)s linked to 5-fluorouracil via a urethane or urea bond.

Abstract: In order to provide a macromolecular prodrug of 5-fluorouracil (5FU) with reduced side-effects and exhibiting strong antitumor activity, 5FU was covalently linked to poly(ethylene glycol) (PEG) via a urethane or urea bond For the purpose of evaluating the release behavior of 5FU, the hydrolysis of the urethane or urea bond in the obtained conjugate of PEG-end capped with 5FU was investigated in vitro at 37 degrees C in aqueous solution media The survival effect for the conjugate was assessed in vivo against p388 lymphocytic leukemia in female CDF1 mice by intraperitoneal (ip) transplantation/ip injection The effects of a hydrophobic hexamethylene spacer group, the end group and the number n of ethylene oxide (EO) units in PEG on the release behavior of 5FU and the survival effect were investigated The release rate of 5FU from the 5FU-terminated PEG conjugates via urethane or urea bond was very fast However, it became slow with increasing n of EO units in PEG and was depressed by the introduction of hydrophobic spacer group The 5FU-terminated PEG conjugates obtained exhibited significant survival effects against p388 leukemia mice ip/ip Especially, the methoxy PEG (n = 113)/urethane/hexamethylene/urea/5FU conjugate showed the strongest survival effect among the synthesized 5FU-capped PEG conjugates via urethane or urea bond compared to free 5FU against p388 leukemia mice These conjugates obtained did not display an acute toxicity even in high dose ranges

Molecular modeling of adenosine receptors. I. The ligand binding site on the A1 receptor.

Abstract: The amino acid sequence of the canine adenosine A1 receptor and the atomic coordinates of a structurally related protein, bacteriorhodopsin, were combined to generate a three-dimensional model for the adenosine A1 receptor. This model consists of seven amphipathic alpha-helices, forming a pore that has a rather distinct partition between hydrophobic and hydrophilic regions. Subsequently, a highly potent and selective ligand, N6-cyclopentyladenosine, was docked into this cavity. A binding site is proposed that takes into account the conformational characteristics of the ligand, obtained from indirect modeling studies by the 'active analog approach'. Moreover, it involves two histidine residues that were shown to be important for ligand coordination from chemical modification studies. Finally, the deduced binding site was used to model other potent ligands that could all be accommodated consistent with earlier biochemical and pharmacological findings.