Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions

Gordon, Eric M.; Barrett, Ronald W.; Dower, William J.; Fodor, Stephen P. A.; Gallop, Mark A.

doi:10.1021/jm00036a001

Cited by 1,062 publications

(332 citation statements)

References 16 publications

(19 reference statements)

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“…Endogenous peptide or peptidic ligands for the receptor motif in question may provide a starting point (67). High-throughput screening of large numbers of individual compounds or affinity screening of pools of compounds assembled by combinatorial techniques is another rich source of leads (68,69). Vast libraries of peptides can be created by a number of techniques, including cloning of complex mixtures of combinatorially synthesized oligonucleotides into specialized expression "display" vectors (84), or by solid-phase peptide-synthesis techniques (68,69,74).…”

Section: Structure-based Design Of Antiallergic Drugsmentioning

confidence: 99%

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

Helm

Spivey

Padlan

1997

Allergy

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Section: Structure-based Design Of Antiallergic Drugsmentioning

confidence: 99%

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

Helm

Spivey

Padlan

1997

Allergy

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“…The Clean Energy Project stands out from other computational materials science approaches as it combines conventional modeling with strategies from modern drug discovery [54][55][56][57][58][59][60][61]: CEP features an automated, highthroughput infrastructure for a systematic screening of millions of OPV candidates at a first-principles electronic structure level [62]. It also adopts techniques from cheminformatics [63,64] and heavily relies on data mining [65,66].…”

Section: The Harvard Clean Energy Projectmentioning

confidence: 99%

The Harvard Clean Energy Project: Large-Scale Computational Screening and Design of Organic Photovoltaics on the World Community Grid

Hachmann

Olivares‐Amaya

Atahan-Evrenk

et al. 2011

J. Phys. Chem. Lett.

589

565

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This perspective article introduces the Harvard Clean Energy Project (CEP), a theory-driven search for the next generation of organic solar cell materials. We give a broad overview of its setup and infrastructure, present first results, and outline upcoming developments.CEP has established an automated, high-throughput, in silico framework to study potential candidate structures for organic photovoltaics. The current project phase is concerned with the characterization of millions of molecular motifs using first-principles quantum chemistry. The scale of this study requires a correspondingly large computational resource which is provided by distributed volunteer computing on IBM's World Community Grid. The results are compiled and analyzed in a reference database and will be made available for public use. In addition to finding specific candidates with certain properties, it is the goal of CEP to illuminate and understand the structure-property relations in the domain of organic electronics. Such insights can open the door to a rational and systematic design of future high-performance materials. The computational work in CEP is tightly embedded in a collaboration with experimentalists, who provide valuable input and feedback to the project.

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“…We utilized this FSH-R luciferase reporter assay to screen a collection of small molecule combinatorial libraries representing more than 20 core scaffolds created using solid-phase chemical synthesis methodologies (14,15). Libraries were typically prepared by split synthesis on TentaGel resin equipped with a photocleavable linker (16), and compounds were screened in pools containing 10 -36 compounds at an estimated concentration of 1-5 M/compound.…”

Section: Screening Combinatorial Small Molecule Libraries For Fsh-r Amentioning

confidence: 99%

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists

Yanofsky

Shen²,

Holden

et al. 2006

Journal of Biological Chemistry

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The pituitary glycoprotein hormones, luteinizing hormone and follicle-stimulating hormone (FSH), act through their cognate receptors to initiate a series of coordinated physiological events that results in germ cell maturation. Given the importance of FSH in regulating folliculogenesis and fertility, the development of FSH mimetics has been sought to treat infertility. Currently, purified and recombinant human FSH are the only FSH receptor (FSH-R) agonists available for infertility treatment. By screening unbiased combinatorial chemistry libraries, using a cAMP-responsive luciferase reporter assay, we discovered thiazolidinone agonists (EC 50's ‫؍‬ 20 M) of the human FSH-R. Subsequent analog library screening and parallel synthesis optimization resulted in the identification of a potent agonist (EC 50 ‫؍‬ 2 nM) with full efficacy compared with FSH that was FSH-R-selective and -dependent. The compound mediated progesterone production in Y1 cells transfected with the human FSH-R (EC 50 ‫؍‬ 980 nM) and estradiol production from primary rat ovarian granulosa cells (EC 50 ‫؍‬ 10.5 nM). This and related compounds did not compete with FSH for binding to the FSH-R. Use of human FSH/thyroid-stimulating hormone (TSH) receptor chimeras suggested a novel mechanism for receptor activation through a binding site independent of the natural hormone binding site. This study is the first report of a high affinity small molecule agonist that activates a glycoprotein hormone receptor through an allosteric mechanism. The small molecule FSH receptor agonists described here could lead to an oral alternative to the current parenteral FSH treatments used clinically to induce ovarian stimulation for both in vivo and in vitro fertilization therapy. Follicle-stimulating hormone (FSH)2 is a glycoprotein hormone produced by the anterior pituitary that plays a key role in stimulating ovulation and spermatogenesis. Like other members of the glycoprotein hormone family (luteinizing hormone, chorionic gonadotropin, and thyroid-stimulating hormone (TSH)), FSH is a heterodimeric protein of ϳ30,000 Da that consists of a common ␣-subunit joined noncovalently to a hormone-specific ␤-subunit. FSH activity is mediated through binding to the FSH receptor (FSH-R), which belongs to family I of the large 7-transmembrane-spanning, G protein-coupled receptor (GPCR) superfamily. The glycoprotein hormone receptors are unique among the members of the GPCR family, because they recognize protein hormones and are dominated by a large N-terminal extracellular region (366 amino acids in the case of the FSH-R) that is the predominant site of hormone binding (1, 2) and is required for signal transduction.The binding of FSH to its receptor results in the activation of adenylyl cyclase through heterotrimeric G proteins. Interaction of the activated FSH-R with G s initiates the cAMP signaling cascade (3). The ability of the FSH-R to activate adenylyl cyclase was exploited to generate a Chinese hamster ovary (CHO) FSH-R reporter cell line (4 -6). Screening of a collection...

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Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions

Cited by 1,062 publications

References 16 publications

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

The Harvard Clean Energy Project: Large-Scale Computational Screening and Design of Organic Photovoltaics on the World Community Grid

Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists

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