Comparative Performance Assessment of the Conformational Model Generators Omega and Catalyst:  A Large-Scale Survey on the Retrieval of Protein-Bound Ligand Conformations

Kirchmair, Johannes; Wolber, Gerhard; Laggner, Christian; Langer, Thomas

doi:10.1021/ci060084g

Cited by 153 publications

(258 citation statements)

References 13 publications

(22 reference statements)

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“…The ligand-binding site in this model was defined by the position of the adrenoceptor ligand carazolol present in the 2RH1 complex. Docking studies were carried out using the ␤1-adrenoceptor ligand-binding site with the programs FRED Receptor v. 2.2.3, OMEGA v. 2.2.1 (Kirchmair et al, 2006), FRED v. 2.2.3 (McGann et al, 2003, and VIDA v. 3.0.0, from OpenEye Scientific Software (Santa Fe, NM). Models of inactive and active conformations of the ␤2-adrenoceptor (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of Key Transmembrane Residues in Agonist and Antagonist Actions at the Two Conformations of the Human β1-Adrenoceptor

Baker¹,

Proudman²,

Hawley³

et al. 2008

Mol Pharmacol

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Studies with 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP 12177) at the human ␤1-adrenoceptor have provided evidence for two binding modes or conformations that have markedly different pharmacological properties. Here, key transmembrane residues (Asp104, Asp138, Ser228, Ser229, Ser232, Phe341, Asn344 and Asn363) have been mutated to provide structural insights into the nature of these conformations. [3 H]CGP 12177 binding and cAMP response element-mediated reporter gene studies confirmed that CGP 12177 was a neutral antagonist (log K D ϭ Ϫ9.18) at the "catecholamine site" and an agonist at the "CGP 12177 site" (log EC 50 ϭ Ϫ8.12). Agonist responses to isoprenaline and CGP 12177 had different sensitivities to ␤1-antagonists (e.g., CGP 20712A; log K D ϭ Ϫ8.65 and Ϫ7.26, respectively). Site-directed mutagenesis showed that Asn363 and Asp138 were key residues for binding of agonists and antagonists, and they were also essential for the agonist actions of CGP 12177. S228A and S229A in transmembranespanning region (TM) 5 reduced the binding of CGP 12177 and had an identical effect on its agonist and antagonist actions. Both N344A and F341A in TM6 abolished the ability of CGP 20712A to discriminate between responses elicited by isoprenaline and CGP 12177. The fact that both Asp138 and Asn363 are absolutely required for CGP 12117 binding in both agonist and antagonist modes leads to the conclusion that the secondary agonist binding site for CGP 12117 must overlap with the catecholamine binding site. Modeling studies provide a basis for these overlapping sites with either the tert-butylamino group or the hydroxyethyloxy and imidazolone portions of CGP 12177 capable of forming polar interactions with Asp138 and Asn363.The ␤1 and ␤2-adrenoceptors are classic examples of G protein-coupled receptors (GPCRs) that couple to G␣ S G-proteins and stimulate adenylyl cyclase activity (Kobilka, 2007). Recent studies of the human and rodent ␤1-adrenoceptors, however, have shown that this receptor exists in at least two conformations that have markedly different pharmacological properties (Granneman, 2001). The initial evidence for multiple binding conformations on the ␤1-adrenoceptor came from detailed studies with the aryloxypropanolamine CGP 12177 (Pak and Fishman, 1996). This compound is a high-affinity neutral antagonist of the classic "catecholamine" binding site or conformation of the ␤1-adrenoceptor; at higher concentrations, however, it activates a secondary site or conformation and produces an agonist response that is relatively resistant to antagonism by other classic ␤-antagonists such as CGP 20712A and propranolol (Pak and Fishman, 1996;Konkar et al., 2000;Baker et al., 2003).Many of our thoughts concerning the specific sites of interaction of ligands with the ␤-adrenoceptors have come from site-directed mutagenesis studies of the ␤2-adrenoceptor. The main binding conformations for catecholamines at the ␤2-adrenoceptor have been identified as Asp113 in tra...

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Section: Discussionmentioning

confidence: 99%

Role of Key Transmembrane Residues in Agonist and Antagonist Actions at the Two Conformations of the Human β1-Adrenoceptor

Baker¹,

Proudman²,

Hawley³

et al. 2008

Mol Pharmacol

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“…A set of 3D conformers for each compound in the database was generated with OMEGA v2.2 [14] using the default settings, while for the query ligand, a single conformer was generated using more restrictive conditions [15]. It followed a shape-based overlay of conformers of each candidate molecule from the database to the query molecule with ROCS [14].…”

Section: Ligand-based Virtual Screeningmentioning

confidence: 99%

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

et al. 2009

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The ligand-based virtual screening of an original chemical library, using atypical antipsychotics as query compounds led to the identification of a novel scaffold with inhibitory activity at the 5-HT 2A serotonin receptor. The hit compounds were confirmed by pharmacological evaluation at the 5-HT 2A receptor and complemented by the selection of other representatives of the same chemical family within our chemical library. A promising scaffold of 6-(pyperazin-1-yl) purine was identified, and the binding mode is illustrated with an automated docking exploration on a homology built model of the 5-HT 2A receptor. The present results constitute an excellent starting point for the discovery of new chemical entities with antipsychotic activity.Schizophrenia is a severe disorder that affects around 24 million people worldwide, typically beginning in late adolescence or early adulthood. It constitutes one of the major psychiatric disorders in the world, and it can impair functioning through the loss of the acquired capability of earning ones own livelihood or through the disruption of studies [1]. Up to date, pharmacological therapy with antipsychotics constitutes the most effective way to maintain most of the symptoms under control. Nowadays, clozapine, discovered nearly 50 years ago, remains as the gold standard antipsychotic, being the only licensed drug indicated for treatment-resistant schizophrenia. However, its use is restricted to these cases mainly due to the risk of agranulocytosis, its major adverse effect [2]. Based on its high affinity at the serotonin 5-HT 2A receptors, modulating its intermediate affinity over dopamine D 2 receptor, a putative mechanism of action of the so-called atypical antipsychotic drugs has been primary established by the Meltzer index, which is the relationship between the affinities at the aforementioned receptors [3]. However, recent multirreceptorial profiling of clozapine has shown its affinity at several aminergic G protein-coupled receptors (GPCRs) [4], opening a new scenario where the beneficial effects of atypical antipsychotics on cognition, negative symptoms, and the low incidence of EPS are mediated by a complex blend of interactions. Therefore, there has been growing interest in the discovery of new compounds that exhibit a similar pharmacological profile as clozapine, but possessing clozapine-unrelated chemical structures.Three dimensional ligand-based virtual screening (3D-LBVS) represents a good strategy to retrieve original, chemically different compounds from a chemical database, displaying similar pharmacological profile to a given compound with clinical interest [5,6]. This statement is not in disagreement with the excellent performance of 2D-based LBVS methodologies, as it has been noted by several authors [6,7]. For the particular case of antipsychotics, however, 3D-LBVS appears as an especially well suited technique attending to the following reasons: i) The target proteins are several aminergic receptors of the GPCR superfamily. Even if the traditional h...

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“…9,11,12 For each molecule, all single bonds except those in small rings were treated as rotatable, and the fragments were identified after removing these rotatable bonds from the molecule. The 3D conformations of the fragments were retrieved from a fragment library.…”

Section: Implementation and Testingmentioning

confidence: 99%

Self‐organizing superimposition algorithm for conformational sampling

Zhu¹,

Agrafiotis²

2007

J Comput Chem

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A novel self-organizing algorithm for conformational sampling is introduced, in which precomputed conformations of rigid fragments are used as templates to enforce the desired geometry. Starting from completely random coordinates, the algorithm repeatedly superimposes the templates to adjust the positions of the atoms, thereby gradually refining the conformation of the molecule. Combined with pair-wise adjustments of the atoms to resolve steric clashes, conformations that satisfy all geometric constraints can be generated from this procedure. The algorithm is demonstrated to achieve good performance and promises potential applications on more challenging modeling problems.

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Comparative Performance Assessment of the Conformational Model Generators Omega and Catalyst: A Large-Scale Survey on the Retrieval of Protein-Bound Ligand Conformations

Cited by 153 publications

References 13 publications

Role of Key Transmembrane Residues in Agonist and Antagonist Actions at the Two Conformations of the Human β1-Adrenoceptor

Role of Key Transmembrane Residues in Agonist and Antagonist Actions at the Two Conformations of the Human β1-Adrenoceptor

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

Self‐organizing superimposition algorithm for conformational sampling

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