My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

Zhou, Yadi; Zhao, Junfei; Fang, Jiansong; Martin, William R.; Li, Lang; Nussinov, Ruth; Chan, Timothy A.; Eng, Charis; Cheng, Feixiong

doi:10.1186/s13059-021-02269-3

Cited by 14 publications

(7 citation statements)

References 69 publications

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“…Connecting allosteric residues with certain pathological conditions and delineating potential underlying mechanisms are receiving increasing interest in modern medicine, especially with the availability of ever-expanding clinical sequencing data. 27,100,[125][126][127][128] Such work can uncover novel therapeutic targets and boost precision diagnosis and personalized medicine treatments.…”

Section: Pathological Implication Of Allosteric Residuesmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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Allostery is a universal, biological phenomenon in which orthosteric sites are finetuned by topologically distal allosteric sites triggered by perturbations, such as ligand binding, residue mutations, or post-translational modifications. Allosteric regulation is implicated in a variety of physiological and pathological conditions and is thus emerging as a novel avenue for drug discovery. Allosteric drugs have traditionally been discovered by serendipity through large-scale experimental screening. Recently, we have witnessed significant progress in biophysics, particularly in structural bioinformatics, which has facilitated the in-depth characterization of allosteric effects and the accurate detection of allosteric residues and exosites. These advances improve our understanding of allosterism and promote allosteric drug discovery, thereby revolutionizing the shift from the traditional serendipitous route used to discover allosteric drugs to the updated path centered on rational structure-based design. In this review, recent advances in computational methods applied to allosteric drug discovery are summarized. We comprehensively review these achievements along various levels of allosteric events, from the construction of allosteric databases to the identification and analysis of allosteric residues, signals, sites, and modulators. We expect to increase the awareness of the discovery of allosteric drugs using structure-based computational methods.

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Section: Pathological Implication Of Allosteric Residuesmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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“…338 The massive genome sequencing data facilitated oncological drug discovery and a comprehensive database, My Personal Mutanome, was constructed for accelerating the development of precision cancer medicine protocols. 339 A strategy that forecasts the emerging proliferation pathway and the specific proteins based on high-resolution chromatin maps can be immensely useful. New highresolution electron microscopy techniques which can image promoter regions of oncogenes are making this feasible 323 obtaining more accurate and deliberate targeting of specific cancers at a fraction of the cost.…”

Section: Double Mutations On the Same Allele Can Results In Dramatic ...mentioning

confidence: 99%

“…The National Cancer Institute assembled and made available drug combinations, many of which have been tested 338 . The massive genome sequencing data facilitated oncological drug discovery and a comprehensive database, My Personal Mutanome, was constructed for accelerating the development of precision cancer medicine protocols 339 . A strategy that forecasts the emerging proliferation pathway and the specific proteins based on high‐resolution chromatin maps can be immensely useful.…”

Section: Precision Oncology Decisions: the Cellular Network Is A Chie...mentioning

confidence: 99%

Mechanism of activation and the rewired network: New drug design concepts

Nussinov

Zhang

Maloney

et al. 2021

Medicinal Research Reviews

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Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.

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“…The latter, targeting protein–protein interactions, has been a particularly attractive goal in preclinical studies ( Lu et al 2020 ). Recent research has made substantial progress in identifying oncogenic and potentially targetable protein interactions ( Cheng et al 2021 ; Zhou et al 2021 ), yet the drug design of the medicinal protein–protein interaction has been largely limited by the lack of high-resolution protein interface structures ( Lu et al 2020 ). As more resources are suggested to put into the structural studies of the implicated protein interactions, we expect more of our interface predictions to be validated and/or improved to further narrow the gap between network medicine and precision medicine.…”

Section: Discussionmentioning

confidence: 99%

A full-proteome, interaction-specific characterization of mutational hotspots across human cancers

et al. 2021

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Rapid accumulation of cancer genomic data has led to the identification of an increasing number of mutational hotspots with uncharacterized significance. Here we present a biologically informed computational framework that characterizes the functional relevance of all 1107 published mutational hotspots identified in approximately 25,000 tumor samples across 41 cancer types in the context of a human 3D interactome network, in which the interface of each interaction is mapped at residue resolution. Hotspots reside in network hub proteins and are enriched on protein interaction interfaces, suggesting that alteration of specific protein–protein interactions is critical for the oncogenicity of many hotspot mutations. Our framework enables, for the first time, systematic identification of specific protein interactions affected by hotspot mutations at the full proteome scale. Furthermore, by constructing a hotspot-affected network that connects all hotspot-affected interactions throughout the whole-human interactome, we uncover genome-wide relationships among hotspots and implicate novel cancer proteins that do not harbor hotspot mutations themselves. Moreover, applying our network-based framework to specific cancer types identifies clinically significant hotspots that can be used for prognosis and therapy targets. Overall, we show that our framework bridges the gap between the statistical significance of mutational hotspots and their biological and clinical significance in human cancers.

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My personal mutanome: a computational genomic medicine platform for searching network perturbing alleles linking genotype to phenotype

Cited by 14 publications

References 69 publications

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Mechanism of activation and the rewired network: New drug design concepts

A full-proteome, interaction-specific characterization of mutational hotspots across human cancers

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