Principal Component Analysis Differentiates the Receptor Binding Profiles of Three Antipsychotic Drug Candidates from Current Antipsychotic Drugs

Lange, Jos H.M.; Reinders, Jan-Hendrik; Tolboom, Jeroen; Glennon, Jeffrey; Coolen, H.K.A.C.; Kruse, Chris G.

doi:10.1021/jm070516u

Cited by 18 publications

(18 citation statements)

References 53 publications

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“…Notwithstanding these promising preliminary results obtained with MAntA, we recognized that engagement of the dopamine D 2 receptor by 1-4 would constitute a significant liability (Figure 2 B). As a consequence, we envisaged that increasing the [15] 2 3570 AE 40 1214961 0.57 8.0 [16] 3 7109 AE 1722 209324 0.37 7.3 [17] 4 1051 AE 61 196514 0.31 9.0 [15] [a] Functional cell-based assay (IP1 quantification by HTRF detection, see SI); [b] "CHEMBL" prefix omitted from ID; [c] Tanimoto similarity index calculated with Morgan substructure fingerprints (radius = 4, 2048 bit). SD: standard deviation (n = 3).…”

Section: Methodsmentioning

confidence: 99%

Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

et al. 2014

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We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.

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Section: Methodsmentioning

confidence: 99%

Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

et al. 2014

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“…[11,12] Table 1 lists experimentally measured binding affinities of clozapine and olanzapine for the receptors studied. [13,14] A close inspection of these affinity values shows that they are significantly higher for the receptors with a serine residue at position 3.36 than those with cysteine at the same position (Student t test, p < 0.001), as shown in Figure 3. For clozapine, the average decrease in affinity associated with the S3.36C substitution is 0.8 log units, whereas this decrease is 1.0 for olanzapine.…”

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confidence: 95%

“…This new structure presents many advantages over the structure of bovine rhodopsin (PDB code: 1F88), [8] Res. 3.36 pK i olanzapine [13] pK i clozapine [13] 5-HT 2A 10 [a] Percentage of pairwise sequence identity for the binding site residues [e] Binding data obtained for the rat receptor, which differs in primary sequence from the human isoform in the active site; in brackets: binding data for the human receptor taken from the PDSP database. [14] eling of G-protein-coupled receptors (GPCRs).…”

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confidence: 99%

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template

et al. 2008

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Schizophrenia is a devastating mental disorder that has a large impact on the quality of life for those who are afflicted and is very costly for families and society.[1] Although the etiology of schizophrenia is still unknown and no cure has yet been found, it is treatable, and pharmacological therapy often produces satisfactory results. Among the various antipsychotic drugs in use, clozapine is widely recognized as one of the most clinically effective agents, even if it elicits significant side effects such as metabolic disorders and agranulocytosis. Clozapine and the closely related compound olanzapine are good examples of drugs with a complex multi-receptor profile; [2] they have affinities toward serotonin, dopamine, a adrenergic, muscarinic, and histamine receptors, among others.Experimental evidence suggests that a complex binding profile is linked to the clinical efficacy of antipsychotic drugs, and indeed, some of the latest efforts in the development of novel antipsychotic drugs [3] are aimed at obtaining compounds with clozapine-like binding affinities for a certain number of receptors: D 2 , D 3 , 5-HT 2A , 5-HT 2C , 5-HT 6 . Unfortunately, our current understanding of which receptors are relevant for the clinical efficacy of antipsychotic agents is based only on the study of a handful of drugs. At this stage, a clear discrimination between clinically useful receptors and those responsible for adverse effects is not possible, as this would require a more thorough understanding of subtle modulating effects, and this is still obscure. Even if the ideal multi-receptor binding profile was known, the problem of how to obtain ligands with such binding specificity would still remain open. A good starting point is to improve our understanding of the structural features associated with binding profiles, thus leading to clinically useful drugs.In this work, we made use of the recently reported structure of the human b 2 adrenergic receptor as a template to build models for a set of receptors that are putatively important for the pharmacological properties of antipsychotic drugs. The aim of this study is to identify characteristics of the complexes of such receptors with clozapine and olanzapine that can explain the excellent clinical behavior of these two drugs. Remarkably, docking studies with homology models based on the new template reveal a binding complex that is different from previously reported complexes for clozapine-like ligands. [4,5] In the first step, we studied the binding affinities of both olanzapine and clozapine for all the receptors in order to identify their common binding profile and the structural features associated with this profile. We then studied the structural differences between the drug-receptor complexes for both antipsychotic drugs that could be responsible for the observed differences in their pharmacological behavior.For this, structural models for a set of 14 receptors that are potentially involved in the pharmacological profile of antipsychotic drugs (Table 1) were generated b...

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“…Silvestre and Prous (2005) published a study in which the application of statistical methods provided robust evidence about the association of M 3 receptor binding affinity and diabetes type 2 risk. Later, PCA was used on a matrix of binding affinity profiles for a mixed set of nine clinically used APDs and three new drug candidates to identify similarity patterns of the compounds (Lange et al, 2007). Our method presented here has the advantage of introducing for the first time a multilevel approach, able to interconnect different types of description of actors (ligands and receptors) that are involved in the pharmacological effects.…”

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confidence: 99%

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

Selent

Bauer-Mehren²,

López³

et al. 2010

Molecular Pharmacology

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The present work introduces a novel method for drug research based on the sequential building of linked multivariate statistical models, each one introducing a different level of drug description. The use of multivariate methods allows us to overcome the traditional one-target assumption and to link in vivo endpoints with drug binding profiles, involving multiple receptors. The method starts with a set of drugs, for which in vivo or clinical observations and binding affinities for potentially relevant receptors are known, and allows obtaining predictions of the in vivo endpoints highlighting the most influential receptors. Moreover, provided that the structure of the receptor binding sites is known (experimentally or by homology modeling), the proposed method also highlights receptor regions and ligandreceptor interactions that are more likely to be linked to the in vivo endpoints, which is information of high interest for the design of novel compounds. The method is illustrated by a practical application dealing with the study of the metabolic side effects of antipsychotic drugs. Herein, the method detects related receptors confirmed by experimental results. Moreover, the use of structural models of the receptor binding sites allows identifying regions and ligand-receptor interactions that are involved in the discrimination between antipsychotic drugs that show metabolic side effects and those that do not. The structural results suggest that the topology of a hydrophobic sandwich involving residues in transmembrane helices (TM) 3, 5, and 6, as well as the assembling of polar residues in TM5, are important discriminators between target/antitarget receptors. Ultimately, this will provide useful information for the design of safer compounds inducing fewer side effects.The classic formulation in which a disease is associated to a single biological receptor is clearly an oversimplification, valid only for exceptional situations. Recent advances in genomics, proteomics, and systems biology depict a far more complex scenario, much less comfortable to work with, in which the biochemical mechanisms of diseases and therapies involve many different biological receptors linked in complex interaction pathways, which are usually poorly understood. The best possible therapies for many complex diseases will probably require a deep and detailed understanding of those relationships. However, because of the extreme complexity of the involved mechanisms, we will not achieve such detailed understanding in the immediate future. Hence, there is a need for new methodological approaches that are able to advance in this way. In this work, we propose a novel method for exploiting pharmacologic information obtained for sets of currently available drugs that are known to interact with multiple related receptors. This method is intended to improve our understanding of the biological mechanisms implicated in the pharmacological treatments but also to provide hints about how the chemical structure of the studied drugs could be improve...

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Principal Component Analysis Differentiates the Receptor Binding Profiles of Three Antipsychotic Drug Candidates from Current Antipsychotic Drugs

Cited by 18 publications

References 53 publications

Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

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Principal Component Analysis Differentiates the Receptor Binding Profiles of Three Antipsychotic Drug Candidates from Current Antipsychotic Drugs

Cited by 18 publications

References 53 publications

Multidimensional De Novo Design Reveals 5‐HT2B Receptor‐Selective Ligands

Multidimensional De Novo Design Reveals 5‐HT2B Receptor‐Selective Ligands

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β2 Adrenergic Receptor Template

A Novel Multilevel Statistical Method for the Study of the Relationships between Multireceptorial Binding Affinity Profiles and In Vivo Endpoints

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Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template