Achbp Fragment Hit
نویسندگان
چکیده
Our constructed ligand efficiency (LE) hot spot surface was used as a guide for structure-based optimization of an AChBP fragment hit. This fragment hit was an analogue of a fragment found in the radioligand binding assay performed on Ls-AChBP, described in Chapter 4. The chemical space around this original fragment was explored by SAR-by-catalogue, thereby increasing its affinity and ligand efficiency. It appeared to be difficult to predict a binding mode for the fragment hits, for several equally scored binding modes were obtained. This is a know phenomenon in fragment-based drug discovery which can be contributed to the low affinities and few interaction points fragments usually have. We used the LE hot spot surface (Chapter 6) for binding mode ranking. The fragment was expanded in silico; the docking modes of several virtual analogues helped in constructing a model for growing directions. Three different growing/optimization cycles were taken. The optimized ligand 43 had a 220-times higher affinity with respect to the initial fragment hit, with a comparable molecular weight and thus improved
منابع مشابه
Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors.
Hierarchical in silico screening protocols against the agonist bound acetylcholine binding protein (AChBP) crystal structure were efficient in identifying novel chemotypes for AChBP and the human α7 receptor. Two hit structures were cocrystallized with AChBP revealing intermolecular cation-π interactions with loop C but lacking intermolecular hydrogen bonding. The compounds act as competitive α...
متن کاملFragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.
Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The f...
متن کاملIdentification of novel α7 nicotinic receptor ligands by in silico screening against the crystal structure of a chimeric α7 receptor ligand binding domain
A hierarchical in silico screening procedure using the crystal structure of an agonist bound chimeric α7/Ls-AChBP protein was successfully applied to both proprietary and commercial databases containing drug-like molecules. An overall hit rate of 26% (pK(i) ≥5.0) was obtained, with an even better hit rate of 35% for the commercial compound collection. Structurally novel and diverse ligands were...
متن کاملStructural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP.
The nicotinic acetylcholine receptor (nAChR) is the prototype member of the superfamily of pentameric ligand-gated ion channels. How the extracellular ligand-binding domain coordinates selective binding of ligand molecules to different subtypes of the receptor is unknown at the structural level. Here, we present the 2.2-A crystal structure of a homolog of the ligand-binding domain of the nAChR,...
متن کاملTwo 'Golden Ratio' indices in fragment-based drug discovery.
Fragment-based drug discovery (FBDD) is complementary to high-throughput screening. The approach has two key stages: identifying the starting fragment hit to be developed and generating the lead compound from the starting fragment hit. Here, we provide an overview of FBDD and introduce two indices originally developed at Astellas Pharma. The first is related to the size ratio of fragment hits t...
متن کامل