Structural basis for ligand recognition at the benzodiazepine binding site of GABAA alpha 3 receptor, and pharmacophore-based virtual screening approach.
Given the heterogeneity of GABA(A) receptor, the pharmacological significance of identifying subtype selective modulators is increasingly being recognized. Thus, drugs selective for GABA(A) alpha(3) receptors are expected to display fewer side effects than the drugs presently in clinical use. Hence we carried out 3D QSAR (three-dimensional quantitative structure-activity relationship) studies on a series of novel GABA(A) alpha(3) subtype selective modulators to gain more insight into subtype affinity. To identify the 3D functional attributes required for subtype selectivity, a chemical feature-based pharmacophore, primarily based on selective ligands representing diverse structural classes was generated. The obtained pseudo receptor model of the benzodiazepine binding site revealed a binding mode akin to "Message-Address" concept. Scaffold hopping was carried out across multi-conformational May Bridge database for the identification of novel chemotypes. Further a focused data reduction approach was employed to choose a subset of enriched compounds based on "Drug likeness" and "Similarity-based" methods. These results taken together could provide impetus for rational design and optimization of more selective and high affinity leads with a potential to have decreased adverse effects.
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
R S K
RS
Vijayan
Nanda
N
Ghoshal
D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000032:analysis* / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010793:Phthalazines / Q000737:chemistry; D025341:Principal Component Analysis; D021281:Quantitative Structure-Activity Relationship; D011963:Receptors, GABA-A / Q000737:chemistry*; D015203:Reproducibility of Results
D008024:Ligands; D010793:Phthalazines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C043388:phthalazine