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

被引：32

作者：

Rodrigues, Tiago ^{[1
]}

Hauser, Nadine ^{[1
]}

Reker, Daniel ^{[1
]}

Reutlinger, Michael ^{[1
]}

Wunderlin, Tiffany ^{[2
]}

Hamon, Jacques ^{[2
]}

Koch, Guido ^{[2
]}

Schneider, Gisbert ^{[1
]}

机构：

[1] ETH, Swiss Fed Inst Technol, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland

[2] Novartis AG, NIBR, CH-4056 Basel, Switzerland

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2015年 / 54卷 / 05期

关键词：

computer-assisted molecular design; drug discovery; GPCR; microfluidics; organic synthesis; PROTEIN-COUPLED RECEPTORS; DRUG DISCOVERY; TARGET PREDICTION; CHEMICAL ENTITIES; PHARMACOLOGY; POTENT; ANTAGONISTS; PROFILES; CHANNELS; AFFINITY;

D O I：

10.1002/anie.201410201

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：1551 / 1555

页数：5

共 46 条

[1] Special Issue: Guide to Receptors and Channels, 5th Edition Abstracts
Alexander, Stephen P. H.
Mathie, Alistair
Peters, John A.
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 2011, 164 : S1 - +
[2] Alexander SPH, 2009, BRIT J PHARMACOL, V158, pS1, DOI 10.1111/j.1476-5381.2009.00499.x
[3] New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
Baell, Jonathan B.
Holloway, Georgina A.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) : 2719 - 2740
[4] An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression
Becker, Oren M.
Dhanoa, Dale S.
Marantz, Yael
Chen, Dongli
Shacham, Sharon
Cheruku, Srinivasa
Heifetz, Alexander
Mohanty, Pradyumna
Fichman, Merav
Sharadendu, Anurag
Nudelman, Raphael
Kauffman, Michael
Noiman, Silvia
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (11) : 3116 - 3135
[5] Drug discovery in the next decade: innovation needed ASAP
Bennani, Youssef L.
[J]. DRUG DISCOVERY TODAY, 2011, 16 (17-18) : 779 - 792
[6] The Expanded Biology of Serotonin
Berger, Miles
Gray, John A.
Roth, Bryan L.
[J]. ANNUAL REVIEW OF MEDICINE, 2009, 60 : 355 - 366
[7] Automated design of ligands to polypharmacological profiles
Besnard, Jeremy
Ruda, Gian Filippo
Setola, Vincent
Abecassis, Keren
Rodriguiz, Ramona M.
Huang, Xi-Ping
Norval, Suzanne
Sassano, Maria F.
Shin, Antony I.
Webster, Lauren A.
Simeons, Frederick R. C.
Stojanovski, Laste
Prat, Annik
Seidah, Nabil G.
Constam, Daniel B.
Bickerton, G. Richard
Read, Kevin D.
Wetsel, William C.
Gilbert, Ian H.
Roth, Bryan L.
Hopkins, Andrew L.
[J]. NATURE, 2012, 492 (7428) : 215 - +
[8] RS-127445:: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist
Bonhaus, DW
Flippin, LA
Greenhouse, RJ
Jaime, S
Rocha, C
Dawson, M
Van Natta, K
Chang, LK
Pulido-Rios, T
Webber, A
Leung, E
Eglen, RM
Martin, GR
[J]. BRITISH JOURNAL OF PHARMACOLOGY, 1999, 127 (05) : 1075 - 1082
[9] Reducing safety-related drug attrition: the use of in vitro pharmacological profiling
Bowes, Joanne
Brown, Andrew J.
Hamon, Jacques
Jarolimek, Wolfgang
Sridhar, Arun
Waldron, Gareth
Whitebread, Steven
[J]. NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (12) : 909 - 922
[10] Elvira KS, 2013, NAT CHEM, V5, P905, DOI [10.1038/NCHEM.1753, 10.1038/nchem.1753]

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