The ensemble approach to distance geometry: application to the nicotinic pharmacophore

Abstract

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.

Methyllycaconitine: a selective probe for neuronal α‐bungarotoxin binding sites

“…1, arrow l), that is likely to be a key moiety in conferring cholinergic nicotinic ac- tivity on this structure. This electronegative centre is a feature of nicotinic ligands, and is considered to be involved in hydrogen bonding with key residues at the recognition site [20]. In addition, this pharmacophore model [20] of nicotinic ligands includes an electrostatic interaction between the quaternary nitrogen of acetylcholine and the receptor binding site.…”

“…This electronegative centre is a feature of nicotinic ligands, and is considered to be involved in hydrogen bonding with key residues at the recognition site [20]. In addition, this pharmacophore model [20] of nicotinic ligands includes an electrostatic interaction between the quaternary nitrogen of acetylcholine and the receptor binding site. Using the rigid agonist cytisine as a definitive template, acetylcholine and MLA were superimposed to generate the conformations illustrated in Fig.…”

Asymmetric Chloronicotinyl Insecticide, 1-[1-(6-Chloro-3-pyridyl)ethyl]- 2-nitroiminoimidazolidine: Preparation, Resolution and Biological Activities toward Insects and Their Nerve Preparations

“…Based on the accumulated structures of this class, several pharmacophore models have been proposed 20,[24][25][26] by referring to the previous models for nAChR agonists. 27,28) These models commonly require two elements, a) a nitrogen atom conjugated to a strongly electron-withdrawing group like a nitroimino moiety and b) a hydrogen-bond acceptor like the pyridine nitrogen atom at a 4-5 Å internitrogen distance. The nitrogen atom signiˆed in a) is electron deˆcient and has an electronic nature common to the pyrrolidinyl nitrogen of nicotine or to the ‰agpole nitrogen of epibatidine which is fully ionized to the ammonium ion in the physiological ‰uid.…”

N-n-Alkylnicotinium Analogs, A Novel Class of Nicotinic Receptor Antagonist: Inhibition ofS(−)-Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices

“…The pA 2 derived from the x-intercept of the Schild regression was Ϫ7.096, providing a respective K i value for NONI of 80.2 nM. The latter K i value from the Schild analysis was 8-fold lower than the IC 50 value obtained for NONI inhibition of Compared with agonist molecules, it has been proposed that antagonists, which are generally large molecules, dock onto the agonist-binding site but extend beyond the region of agonist binding (Sheridan et al, 1986). The additional structural bulk associated with the antagonist molecules is believed to prevent the receptor protein from achieving the open-channel form (Sheridan et al, 1986).…”