Fragment-Based Lead Discovery and Design

Joseph‐McCarthy, Diane; Campbell, Arthur J.; Kern, Günther; Moustakas, Demetri T.

doi:10.1021/ci400731w

Cited by 126 publications

(111 citation statements)

References 121 publications

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“…Identifying and studying the BPs of specific ligands to a group of proteins helps understanding of the molecular mechanisms governing such interactions (23). In turn, this knowledge may help in the design of proteins with specific functions (24,25), and in development of inhibitors and drugs targeting the identified binding region (26). A wide variety of approaches have been developed and employed to address the BP identification problem in silico (recently reviewed in (27)).…”

Section: Introductionmentioning

confidence: 99%

Cardiolipin Interactions with Proteins

Planas-Iglesias

Dwarakanath

Mohammadyani

et al. 2015

Biophysical Journal

124

108

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Cardiolipins (CL) represent unique phospholipids of bacteria and eukaryotic mitochondria with four acyl chains and two phosphate groups that have been implicated in numerous functions from energy metabolism to apoptosis. Many proteins are known to interact with CL, and several cocrystal structures of protein-CL complexes exist. In this work, we describe the collection of the first systematic and, to the best of our knowledge, the comprehensive gold standard data set of all known CL-binding proteins. There are 62 proteins in this data set, 21 of which have nonredundant crystal structures with bound CL molecules available. Using binding patch analysis of amino acid frequencies, secondary structures and loop supersecondary structures considering phosphate and acyl chain binding regions together and separately, we gained a detailed understanding of the general structural and dynamic features involved in CL binding to proteins. Exhaustive docking of CL to all known structures of proteins experimentally shown to interact with CL demonstrated the validity of the docking approach, and provides a rich source of information for experimentalists who may wish to validate predictions.

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Section: Introductionmentioning

confidence: 99%

Cardiolipin Interactions with Proteins

Planas-Iglesias

Dwarakanath

Mohammadyani

et al. 2015

Biophysical Journal

124

108

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“…Multiple research groups have focused on the allosteric regulation of mGlu 5 , for example, Andreas Ritzen’s group and P. Jefferey Conn’s group designed and synthesized a series of allosteric ligands for mGlu 5 (19). Although a classical structure-based medicinal chemistry approach could be useful for the generation of corresponding allosteric modulators, state-of-the-art computational methods could also be powerful tools in generating new ideas in allosteric modulator design in this field (20,21). …”

Section: Introductionmentioning

confidence: 99%

“…There are several ways that fragment-based approach could be applied to drug discovery: (1) binding sites and pharmacophores identification for receptor binding could be achieved with fragment screening techniques; (2) HTS libraries could be biased and the optimization of lead compounds could be guided with fragments screening hits; (3) leads with the potential to be optimized into drug-like compounds can be identified with fragment screening (21–25). Fragment binding can reveal hot spots on proteins, which could result in high-affinity receptor-ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

Bian

Feng

Yang

et al. 2017

AAPS J

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GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases. The crystal structure of mGlu5 in the complex with the negative allosteric modulator mavoglurant was recently reported, providing a fundamental model for designing new allosteric modulators. Computational fragment-based drug discovery represents a powerful scaffold-hopping and lead structure-optimization tool for drug design. In the present work, a set of integrated computational methodologies was first used, such as fragment library generation and retrosynthetic combinatorial analysis procedure (RECAP) for novel compound generation. Then, the compounds generated were assessed by benchmark dataset verification, docking studies, and QSAR model simulation. Subsequently, structurally diverse compounds, with reported or unreported scaffolds, can be observed from top 20 in silico synthesized compounds, which were predicted to be potential mGlu5 modulators. In silico compounds with reported scaffolds may fill SAR holes in known, patented series of mGlu5 modulators. And the generation of compounds without reported tests on mGluR indicates that our approach is doable for exploring and designing novel compounds. Our case study of designing allosteric modulators on mGlu5 demonstrated that the established computational fragment-based approach is a useful methodology for facilitating new compound design in the future.

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“…Venetoclax was the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein [22] . In research, docking-based fragment screening and fragment reassembly, ie, fragment growing, fragment linking and fragment merging, were also applied and exhibited high efficiency in lead discovery and optimization [23] . In addition to virtual screening programs, computational approaches have been developed to facilitate fragment reassembly.…”

Section: Introductionmentioning

confidence: 99%

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors

Wang

Zhu

et al. 2017

Acta Pharmacol Sin

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The mutation of B-Raf is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf is an ideal drug target. This study focused on developing novel B-Raf inhibitors as drug leads against various cancers with B-Raf mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf inhibitors. A highly potent fragment binding to the hinge area of B-Raf was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf inhibitor with an IC value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-Raf was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

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Fragment-Based Lead Discovery and Design

Cited by 126 publications

References 121 publications

Cardiolipin Interactions with Proteins

Cardiolipin Interactions with Proteins

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors

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