A computational study of the binding of 3-(arylidene) anabaseines to two major brain nicotinic acetylcholine receptors and to the acetylcholine binding protein.
Nicotinic acetylcholine receptors (nAChRs) have become targets for drug development in recent years. 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA), which selectively stimulates the alpha7 nAChR, has been shown to alleviate some cognitive deficits associated with schizophrenia. In this paper we report an analysis of the interactions between 47 arylidene-anabaseines (including 45 benzylidene-anabaseines) and rat brain alpha7 and alpha4beta2 nicotinic acetylcholine receptors, using three different modeling techniques, namely 2D-QSAR, 3D-QSAR and molecular docking to the Aplysia californica acetylcholine binding protein (AChBP), a water soluble, homomeric nAChR surrogate receptor with a known crystal structure. Our investigation indicates the importance of: (1) the nitrogen atom of the tetrahydropyridyl (THP) ring for hydrogen bond formation; (2) pi-pi interactions between the aromatic rings of the ligands and the nAChBP binding site; (3) molecular surface recognition expressed in terms of steric complimentarity. On the basis of the 3D-QSAR results, bulky substituents at positions 2 (and due to the rotational freedom also at position 6) and 4 of the benzylidene moiety, with highly electronegative atoms projecting approximately 3-3.5A away from the benzylidene ring at position 4 seem optimal for enhancing binding affinity to the alpha7 nAChR.
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
Svetoslav H
SH
Slavov
Maksim
M
Radzvilovits
Susan
S
LeFrancois
Iva B
IB
Stoyanova-Slavova
Ferenc
F
Soti
William R
WR
Kem
Alan R
AR
Katritzky
D000691:Anabasine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001048:Aplysia; D001921:Brain; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D008958:Models, Molecular; D008968:Molecular Conformation; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002352:Carrier Proteins; C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C091713:anabaseine; D000691:Anabasine