Computational methods-guided design of modulators targeting protein-protein interactions (PPIs)

Qiu, Yuran; Li, Xinyi; He, Xinheng; Pu, Jun; Zhang, Jian; Lu, Shaoyong

doi:10.1016/j.ejmech.2020.112764

Cited by 28 publications

(20 citation statements)

References 156 publications

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“…The detection of allosteric sites, a pre-requisite for allosteric drug development, represents a major obstacle. Historically, allosteric site prediction was once based on serendipitous discovery, while the latest decade has witnessed the upsurge of computational tools aiding the structure-based rational design of allosteric regulators [ 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Due to a constantly deepening understanding of protein allostery, and the rapid development of diverse bioinformatics methodologies, the characterization and identification of potential allosteric sites was considerably facilitated.…”

Section: Discussionmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFRL858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.

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Section: Discussionmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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“…Molecular docking became a common method for bioactivity and drug design studies [38,39]. In many published texts, experimental studies are supported by computational methods such as molecular docking [40,41]. The action mechanisms and interactions of the molecules with biological macromolecules such as proteins and enzymes can be analyzed with this method.…”

Section: Resultsmentioning

confidence: 99%

Analysis of Interactions of NHC Type Molecules and NHC-Ag Complexes with VEGFR-2 and DNA: A Molecular Docking Study

Üstün¹,

Şahin²

2021

Adıyaman University Journal of Science

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Molecular docking is an important tool in drug research. Thanks to these calculations, the type and magnitude of interactions of the molecules with target molecules are evaluated. It is also possible to perform more detailed analyzes than known experimental methods in an easy and economical way by using the results obtained with current scientific developments and examine interactions with different target molecules depending on bioactivity type. Cancer researches show that vascular endothelial growth factor is effective in the growth and proliferation of cancer cells. Inhibition of the receptor that regulates the release of this factor may be an efficient method for designing an anticancer agent. One of these receptors is VEGFR-2. This receptor can be used as a target molecule in cancer research. In addition, the interaction of molecules with DNA is important in terms of getting insight for future studies. In this study, the interaction of 1-allyl-3benzylbenzimidazolium, 1-allyl-3-(naphthylmethyl)benzimidazolium, 1-allyl-3-(anthracen-9-ylmethyl)benzimidazolium,chloro[1-allyl-3-benzylbenzimidazolium-2-ylidene]silver(I), chloro[1allyl-3-(naphthylmethyl)benzimidazolium-2-ylidene]silver(I), chloro[1-allyl-3-(anthracen-9-ylmethyl)benzimidazolium-2-ylidene]silver(I) with VEGFR-2 and DNA were analyzed by molecular docking methods.

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“…Upon the inhibitor-protein interactions, the protein structures will be subtly altered, which triggers the surface conformational changes, thereby facilitating the more compact binding of the inhibitors. Importantly, the rapid advances in structural biology and computational biology have enabled the in-depth exploration into the sophisticated conformational ensembles of PPI systems (Qiu et al, 2020 ; Wang et al, 2021 ). With the help of techniques such as molecular dynamics (MD) simulations (Yang et al, 2019 ), the transient intermediate PPI interface conformations can be probed, based on which further structure-based rational inhibitor design can be more easily carried out (Tavakoli and Ganjalikhany, 2019 ; Yao et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

Wang

Liu

et al. 2021

Front. Chem.

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Protein-protein interactions (PPIs) are well-established as a class of promising drug targets for their implications in a wide range of biological processes. However, drug development toward PPIs is inevitably hampered by their flat and wide interfaces, which generally lack suitable pockets for ligand binding, rendering most PPI systems “undruggable.” Here, we summarized drug design strategies for developing peptide-based PPI inhibitors. Importantly, several quintessential examples toward well-established PPI targets such as Bcl-2 family members, p53-MDM2, as well as APC-Asef are presented to illustrate the detailed schemes for peptide-based PPI inhibitor development and optimizations. This review supplies a comprehensive overview of recent progresses in drug discovery targeting PPIs through peptides or peptidomimetics, and will shed light on future therapeutic agent development toward the historically “intractable” PPI systems.

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Computational methods-guided design of modulators targeting protein-protein interactions (PPIs)

Cited by 28 publications

References 156 publications

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

Analysis of Interactions of NHC Type Molecules and NHC-Ag Complexes with VEGFR-2 and DNA: A Molecular Docking Study

Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions

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