Fragments, network biology and designing multiple ligands

Morphy, Richard; Rankovic, Zoran

doi:10.1016/j.drudis.2006.12.006

Cited by 195 publications

(177 citation statements)

References 28 publications

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“…In other words, less complex molecules are more prone to bind to multiple proteins due to the lower probability of a mismatch between ligand and the proteins of interest. Along the same lines, Morphy's analysis of Organon's SCOPE database revealed a clear correlation between size and selectivity [15], supporting the hypothesis that the inherent simplicity of small molecules favours non-selective binding events [16]. Moreover, there is ample experimental support for a higher hit rate for fragments in multitarget screening with respect to the larger compounds typically screened in high throughput screening (HTS).…”

Section: Introductionmentioning

confidence: 56%

“…However, if the targets are too different, it may not be possible to grow the fragment in a way that simultaneously improves affinity at each target [17]. Nevertheless, the extent to which affinity must be improved may be lower for an MTDL than for a single-targeted molecule, if strong pharmacodynamic synergy between the targets exists [16].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, there is ample experimental support for a higher hit rate for fragments in multitarget screening with respect to the larger compounds typically screened in high throughput screening (HTS). In this respect, FBDD might also provide more drug-like structures than the large and lipophilic molecules identified through HTS, thus simplifying physicochemical issues related to the hit-and lead-optimization process [16].…”

Section: Introductionmentioning

confidence: 99%

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Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

2016

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Abstract:Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer's disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid-and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.

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Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

2016

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“…In follow up studies by measuring cAMP production, however, NCGC00071837 also was found to both directly stimulate (in the absence of NKH 477) and potentiate (in the presence of NKH 477) cAMP production when PDE inhibition was maximized by the addition of Ro 20-1247. NCGC00071837 was unique in this spectrum of activity, and may therefore be more effective in enhancing CREB signaling than compounds with a single mode of action (38).…”

Section: Application Of a Pathway Assay To Identify Multiple Mechanismentioning

confidence: 99%

Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory

Xia

Huang

Guo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Many studies have implicated the cAMP Response Element Binding (CREB) protein signaling pathway in long-term memory. To identify small molecule enhancers of CREB activation of gene expression, we screened Ϸ73,000 compounds, each at 7-15 concentrations in a quantitative high-throughput screening (qHTS) format, for activity in cells by assaying CREB mediated ␤-lactamase reporter gene expression. We identified 1,800 compounds that potentiated CREB mediated gene expression, with potencies as low as 16 nM, comprising 96 structural series. Mechanisms of action were systematically determined, and compounds that affect phosphodiesterase 4, protein kinase A, and cAMP production were identified, as well as compounds that affect CREB signaling via apparently unidentified mechanisms. qHTS folowed by interrogation of pathway targets is an efficient paradigm for lead generation for chemical genomics and drug development. memory enhancer ͉ phosphodiesterase inhibitor ͉ quantitative high-throughput screening

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“…Although some systems biology approaches have been applied to targets in lead 7 and drug discovery 8,9 within the pharmaceutical industry, this type of general integration of chemistry and systems biology has not yet been seen in academics. However, a tremendous opportunity now exists because academic biomolecular screening efforts, particularly the Molecular Libraries Screening Centers Network (MLSCN) being funded by the NIH Roadmap via the Molecular Libraries Initiative (MLI) 10 have created a wealth of systematic data describing the biological effects of small molecules.…”

mentioning

confidence: 99%

Systems chemical biology

Oprea¹,

et al. 2007

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The increasing availability of data related to genes, proteins and their modulation by small molecules, paralleled by the emergence of simulation tools in systems biology, has provided a vast amount of biological information. However, there is a critical need to develop cheminformatics tools that can integrate chemical knowledge with these biological databases, with the goal of creating systems chemical biology.Hailed as a departure from the "reductionist approach", where investigators dedicate their efforts to the study of a single gene or protein, systems biology is generally regarded as the "comprehensive approach". Large networks describing the regulation of entire genomes, metabolic or signal transduction pathways are analyzed in their totality at different levels of biological organization 1 . Systems biology, which blends theory, computational modeling, and high-throughput experimentation 2 , has already led to advances in the understanding of cell signaling 3 , developmental biology 4 , cell physiology 5 , and metabolic networks 6 . However, despite these advances in biological insight, what is currently lacking from these approaches is any holistic understanding of how small molecules affect biological systems. The introduction of cheminformatics tools that can be seamlessly integrated with currently available bio-and cheminformatic databases and biological network simulations and software will be required to move toward a systematic understanding of the way small molecules impact biological systems -a field which we call "systems chemical biology."Although some systems biology approaches have been applied to targets in lead 7 and drug discovery 8,9 within the pharmaceutical industry, this type of general integration of chemistry and systems biology has not yet been seen in academics. However, a tremendous opportunity now exists because academic biomolecular screening efforts, particularly the Molecular Libraries Screening Centers Network (MLSCN) being funded by the NIH Roadmap via the Molecular Libraries Initiative (MLI) 10 have created a wealth of systematic data describing the biological effects of small molecules. The new data that is being generated is particularly valuable because it extends information beyond the relatively limited number of biological and screening data available from industry to the entire array of macromolecules and macromolecular networks that are being experimentally evaluated in academic laboratories. Via the MLI, the effects of hundreds of thousands of small molecules on biological systems of varied complexity, ranging from screens with purified targets to simultaneous multi-target (multiplex) screens, phenotypic screens, and even whole organism assays, are being investigated. Central to the MLI is public access, and bioassay data from MLSCN screens are being deposited in PubChem, a freely accessible database. This unprecedented effort has created an opportunity to integrate chemical

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Fragments, network biology and designing multiple ligands

Cited by 195 publications

References 28 publications

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory

Systems chemical biology

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