The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Charles H Reynolds - One of the best experts on this subject based on the ideXlab platform.
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validity of Ligand Efficiency metrics
2014Co-Authors: Christopher W Murray, Daniel A Erlanson, Andrew L Hopkins, Gyorgy M Keseru, Paul D Leeson, David C Rees, Charles H Reynolds, Nicola J RichmondAbstract:A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of Ligand Efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic Ligand Efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.
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the role of Ligand Efficiency metrics in drug discovery
2014Co-Authors: Andrew L Hopkins, Gyorgy M Keseru, Paul D Leeson, David C Rees, Charles H ReynoldsAbstract:The judicious application of Ligand or binding Efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized Ligand Efficiency values for their targets. Optimizing Ligand Efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.
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Ligand Efficiency and fragment based drug discovery
2009Co-Authors: Scott D Bembenek, Brett A Tounge, Charles H ReynoldsAbstract:The use of fragment-based drug discovery (FBDD) has increased in recent years since it is more likely to produce a better optimized compound of lower molecular weight. Ligand Efficiency (LE) has become important for assessing fragments, HTS hits, and resulting optimized Ligands. LE is useful for comparing Ligands of equal molecular weight, but is ineffective for comparisons of Ligands of differing molecular weight. LE has a strong dependence on molecular size, which has led us to develop a size-independent Efficiency score termed fit quality. Evaluating FBDD examples from the literature using LE and fit quality, we find that, in general, the LEs of starting fragments are greater than those of larger, more elaborated, structures. Fit quality scores, however, tend to improve upon optimization of the fragments.
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Ligand binding Efficiency trends physical basis and implications
2008Co-Authors: Charles H Reynolds, Brett A Tounge, Scott D BembenekAbstract:Ligand Efficiency (i.e., potency/size) has emerged as an important metric in drug discovery. In general, smaller, more efficient Ligands are believed to have improved prospects for good drug properties (e.g., bioavailability). Our analysis of thousands of Ligands across a variety of targets shows that Ligand Efficiency is dependent on Ligand size with smaller Ligands having greater efficiencies, on average, than larger Ligands. We propose two primary causes for this size dependence: the inevitable reduction in the quality of fit between Ligand and receptor as the Ligand becomes larger and more complex and the reduction in accessible Ligand surface area on a per atom basis as size increases. These results have far-ranging implications for analysis of high-throughput screening hits, fragment-based approaches to drug discovery, and even computational models of potency.
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the role of molecular size in Ligand Efficiency
2007Co-Authors: Charles H Reynolds, Scott D Bembenek, Brett A ToungeAbstract:Ligand Efficiency is a simple metric for assessing whether a Ligand derives its potency from optimal fit with the protein target or simply by virtue of making many contacts. Comparison of protein-Ligand binding affinities for over 8000 Ligands with 28 protein targets shows conclusively that the average Ligand binding affinities are not linear with molecular size. It is therefore important to scale Ligand efficiencies by the size of the Ligand, particularly where small Ligands (e.g., fragments) are involved. We propose a simple 'fit quality' metric that removes this dependence.
Andrew L Hopkins - One of the best experts on this subject based on the ideXlab platform.
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validity of Ligand Efficiency metrics
2014Co-Authors: Christopher W Murray, Daniel A Erlanson, Andrew L Hopkins, Gyorgy M Keseru, Paul D Leeson, David C Rees, Charles H Reynolds, Nicola J RichmondAbstract:A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett. 2014, 5, 2-5) argued that the standard definition of Ligand Efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic Ligand Efficiency (LLE) can be useful during the multiparameter optimization challenge faced by medicinal chemists.
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the role of Ligand Efficiency metrics in drug discovery
2014Co-Authors: Andrew L Hopkins, Gyorgy M Keseru, Paul D Leeson, David C Rees, Charles H ReynoldsAbstract:The judicious application of Ligand or binding Efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized Ligand Efficiency values for their targets. Optimizing Ligand Efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.
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fragment screening by surface plasmon resonance
2010Co-Authors: Iva Navratilova, Andrew L HopkinsAbstract:Fragment-based drug discovery is a validated approach for the discovery of drug candidates. However, the weak affinity of fragment compounds requires highly sensitive biophysical techniques, such as nuclear magnetic resonance (NMR) or X-ray crystallography, to identify hits. Thus the advantages of screening small fragment libraries are partly offset by the high cost of biophysical analyses. Here we present a method for biosensor-based fragment screening using surface plasmon resonance (SPR). In order to reduce the false positive detection rate we present a novel method of data analysis that incorporates multiple referencing with Ligand Efficiency. By implementing all necessary steps for assay design, data analysis and interpretation, SPR-based fragment screening has potential to eliminate all nonspecific (false positive) binders. Therefore, given the advantages of low protein consumption, rapid assay development and kinetic and thermodynamic validation of hits, SPR can be considered as a primary screening technology for fragment-based drug discovery.
Gregor James Macdonald - One of the best experts on this subject based on the ideXlab platform.
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discovery of 3 cyclopropylmethyl 7 4 phenylpiperidin 1 yl 8 trifluoromethyl 1 2 4 triazolo 4 3 a pyridine jnj 42153605 a positive allosteric modulator of the metabotropic glutamate 2 receptor
2012Co-Authors: Jose Maria Cid, Gary Tresadern, Juan Antonio Vega, Ana Isabel De Lucas, Encarnacion Matesanz, Laura Iturrino, Maria Lourdes Linares, Aranzazu Garcia, Jose Ignacio Andres, Gregor James MacdonaldAbstract:Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic Ligand Efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep–wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED50 of 5.4 mg/kg sc, indicative of antipsychotic activity.
Benjamin G Tehan - One of the best experts on this subject based on the ideXlab platform.
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fragment and structure based drug discovery for a class c gpcr discovery of the mglu5 negative allosteric modulator htl14242 3 chloro 5 6 5 fluoropyridin 2 yl pyrimidin 4 yl benzonitrile
2015Co-Authors: John A Christopher, Sarah Joanne Aves, K A Bennett, A S Dore, J C Errey, A Jazayeri, Fiona H Marshall, K Okrasa, Maria Josefa Serranovega, Benjamin G TehanAbstract:Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioLigand binding assay enabled the identification of moderate affinity, high Ligand Efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 A, respectively.
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biophysical fragment screening of the β1 adrenergic receptor identification of high affinity arylpiperazine leads using structure based drug design
2013Co-Authors: John A Christopher, A S Dore, J C Errey, Fiona H Marshall, J D Brown, Markus Koglin, David G Myszka, Rebecca L Rich, Christopher G Tate, Benjamin G TehanAbstract:Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high Ligand Efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein–Ligand crystal structures of the β1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with Ligands derived from fragment screening, structures of the stabilized β1AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 A, respectively.
Miles Congreve - One of the best experts on this subject based on the ideXlab platform.
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fragment based drug discovery applied to hsp90 discovery of two lead series with high Ligand Efficiency
2010Co-Authors: Christopher W Murray, Maria Grazia Carr, Owen Callaghan, Gianni Chessari, Miles Congreve, Suzanna Cowan, Joseph E Coyle, Robert Downham, Eva Figueroa, Martyn FredericksonAbstract:Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good Ligand Efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good Ligand Efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1000000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.
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application of fragment based lead generation to the discovery of novel cyclic amidine beta secretase inhibitors with nanomolar potency cellular activity and high Ligand Efficiency
2007Co-Authors: Philip D Edwards, Owen Callaghan, Gianni Chessari, Jeffrey S Albert, Mark Sylvester, David Aharony, Donald W Andisik, James B Campbell, Robin A E Carr, Miles CongreveAbstract:Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of β-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the Ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a Ligand Efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.