Computational Drug Design Accommodating Receptor Flexibility:  The Relaxed Complex Scheme

Lin, Jiunn-Yuan; Perryman, Alexander L.; Schames, Julie R.; McCammon, J. Andrew

doi:10.1021/ja0260162

Cited by 388 publications

(367 citation statements)

References 17 publications

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“…Expanding the concept of a relaxed complex scheme for structure-based drug discovery (45,46), we built an ensemble of K-Ras conformers that contained infrequently sampled structures. Such structures could potentially harbor open binding sites that are invisible in crystal structures.…”

Section: Methodsmentioning

confidence: 99%

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

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

135

133

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Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.cancer | molecular dynamics | allosteric site | drug design

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Section: Methodsmentioning

confidence: 99%

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

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

135

133

View full text Add to dashboard Cite

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“…The discovery of allosteric modulators with chemically novel structures will undoubtedly increase the potential for better receptor subtype selectivity. Based on the hypothesis that incorporation of receptor flexibility is key to effective GPCR drug design (34,35), we used aMD simulations to construct structural ensembles for molecular docking in the extracellular vestibule of the receptor. Ensemble docking of chemical compounds obtained from the National Cancer Institute (NCI) compound library (36) was performed to identify new potential allosteric modulators.…”

Section: Significancementioning

confidence: 99%

Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

Miao

Goldfeld

Moo

et al. 2016

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

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Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M 2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Institute (NCI) were docked to the receptor ensembles. Retrospective docking of known ligands showed that combining aMD simulations with Glide induced fit docking (IFD) provided much-improved enrichment factors, compared with the Glide virtual screening workflow. Glide IFD was thus applied in receptor ensemble docking, and 38 top-ranked NCI compounds were selected for experimental testing. In [ 3 H]Nmethylscopolamine radioligand dissociation assays, approximately half of the 38 lead compounds altered the radioligand dissociation rate, a hallmark of allosteric behavior. In further competition binding experiments, we identified 12 compounds with affinity of ≤30 μM. With final functional experiments on six selected compounds, we confirmed four of them as new negative allosteric modulators (NAMs) and one as positive allosteric modulator of agonist-mediated response at the M 2 mAChR. Two of the NAMs showed subtype selectivity without significant effect at the M 1 and M 3 mAChRs. This study demonstrates an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies.GPCR | allosteric modulators | ensemble docking | affinity | cooperativity

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“…25 Representative structures extracted from these simulations can be used in conjunction with the relaxed complex scheme, a docking technique that accounts for receptor flexibility. [26][27][28] Alternatively, the pocket-volume analysis makes it possible to extract snapshots from the simulations that exhibit particularly open pocket conformations. Many of these pockets are wider in general, allowing the ligand to assume conformations different from those seen in the crystal structures utilizing many more possible alternative stabilizing interaction.…”

Section: Implications For Drug Discoverymentioning

confidence: 99%

Dynamics of Plasmodium falciparum enoyl‐ACP reductase and implications on drug discovery

Lindert

McCammon

2012

Protein Science

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Enoyl-acyl carrier protein reductase (ENR) is a crucial enzyme in the type II fatty acid synthesis pathway of many pathogens such as Plasmodium falciparum, the etiological agent of the most severe form of malaria. Because of its essential function of fatty acid double bond reduction and the absence of a human homologue, PfENR is an interesting drug target. Although extensive knowledge of the protein structure has been gathered over the last decade, comparatively little remains known about the dynamics of this crucial enzyme. Here, we perform extensive molecular dynamics simulations of tetrameric PfENR in different states of cofactor and ligand binding, and with a variety of different ligands bound. A pocket-volume analysis is also performed, and virtual screening is used to identify potential druggable hotspots. The implications of the results for future drug-discovery projects are discussed.

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Computational Drug Design Accommodating Receptor Flexibility: The Relaxed Complex Scheme

Cited by 388 publications

References 17 publications

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

Dynamics of Plasmodium falciparum enoyl‐ACP reductase and implications on drug discovery

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