The cellular network and its environment govern cell and organism behavior and are fundamental to the comprehension of function, misfunction and drug discovery. Over the last few years, drugs were observed to often bind to more than one target;thus, poly-pharmacology approaches can be advantageous, complementing the """"""""one drug - one target"""""""" strategy. Targeting drug discovery from the systems biology standpoint can help in studies of network effects of mono- and poly-pharmacology. In this mini-review, we provide an overview of the usefulness of network description and tools for mono- and poly-pharmacology, and the ways through which protein interactions can help single- and multi-target drug discovery efforts. We further describe how, when combined with experimental data, modeled structural networks which can predict which proteins interact and provide the structures of their interfaces, can model the cellular pathways, and suggest which specific pathways are likely to be affected. Such structural networks may facilitate structure-based drug design;forecast side effects of drugs;and suggest how the effects of drug binding can propagate in multi-molecular complexes and pathways. We provide an overview of targeted anticancer therapies with small molecule kinase inhibitors. First, we discuss why a single constitutively active kinase emanating from a variety of aberrant genetic alterations is capable of transforming a normal cell, leading it to acquire the hallmarks of a cancer cell. To draw attention to the fact that kinase inhibition in targeted cancer therapeutics differs from conventional cytotoxic chemotherapy, we exploit a conceptual framework explaining why suppressed kinase activity will selectively kill only the so-called oncogene 'addicted'cancer cell, while sparing the healthy cell. Second, we introduce the protein kinase superfamily in light of its common active conformation with precisely positioned structural elements, and the diversified auto-inhibitory conformations among the kinase families. Understanding the detailed activation mechanism of individual kinases is essential to relate the observed oncogenic alterations to the elevated constitutively active state, to identify the mechanism of consequent drug resistance, and to guide the development of the next-generation inhibitors. To clarify the vital importance of structural guidelines in studies of oncogenesis, we explain how somatic mutations in EGFR result in kinase constitutive activation. Third, in addition to the common theme of secondary (acquired) mutations that prevent drug binding from blocking a signaling pathway which is hijacked by the aberrant activated kinase, we discuss scenarios of drug resistance and relapse by compensating lesions that bypass the inactivated pathway in a vertical or horizontal fashion. Collectively, these suggest that the future challenge of cancer therapy with small molecule kinase inhibitors will rely on the discovery of distinct combinations of optimized drugs to target individual subtypes of different cancers. Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88. Allostery is largely associated with conformational and functional transitions in individual proteins. This concept can be extended to consider the impact of conformational perturbations on cellular function and disease states. Here, we clarify the concept of allostery and how it controls physiological activities. We focus on the challenging questions of how allostery can both cause disease and contribute to development of new therapeutics.
We aim to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level and to emphasize the potential of allosteric drugs in innovative therapies. Allosteric propagation results in communication between distinct sites in the protein structure;it also encodes specific effects on cellular pathways, and in this way it shapes cellular response. One example of long-range effects is binding of morphogens to cell surface receptors, which initiates a cascade of protein interactions that leads to genome activation and specific cellular action. Allosteric propagation results from combinations of multiple factors, takes place through dynamic shifts of conformational ensembles, and affects the equilibria of macromolecular interactions. Here, we (a) emphasize the well-known yet still underappreciated role of allostery in conveying explicit signals across large multimolecular assemblies and distances to specify cellular action;(b) stress the need for quantitation of the allosteric effects;and finally, (c) propose that each specific combination of allosteric effectors along the pathway spells a distinct function. The challenges are colossal;the inspiring reward will be predicting function, misfunction, and outcomes of drug regimes. The ubiquitin-proteasome system (UPS) is involved in many cellular processes including protein degradation. Degradation of a protein via this system involves two successive steps: ubiquitination and degradation. Ubiquitination tags the target protein with ubiquitin-like proteins (UBLs), such as ubiquitin, small ubiquitin-like modifier (SUMO) and NEDD8, via a cascade involving three enzymes: activating enzyme E1, conjugating enzyme E2 and E3 ubiquitin ligases. The proteasomes recognize the UBL-tagged substrate proteins and degrade them. Accumulating evidence indicates that allostery is a central player in the regulation of ubiquitination, as well as deubiquitination and degradation. Here, we provide an overview of the key mechanistic roles played by allostery in all steps of these processes, and highlight allosteric drugs targeting them. Throughout the review, we emphasize the crucial mechanistic role played by linkers in allosterically controlling the UPS action by biasing the sampling of the conformational space, which facilitate the catalytic reactions of the ubiquitination and degradation. Finally, we propose that allostery may similarly play key roles in the regulation of molecular machines in the cell, and as such allosteric drugs can be expected to be increasingly exploited in therapeutic regimes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010441-12
Application #
8763102
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$395,608
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Liao, Tsung-Jen; Jang, Hyunbum; Tsai, Chung-Jung et al. (2017) The dynamic mechanism of RASSF5 and MST kinase activation by Ras. Phys Chem Chem Phys 19:6470-6480
Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum (2017) A New View of Pathway-Driven Drug Resistance in Tumor Proliferation. Trends Pharmacol Sci 38:427-437
Andrabi, Munazah; Hutchins, Andrew Paul; Miranda-Saavedra, Diego et al. (2017) Predicting conformational ensembles and genome-wide transcription factor binding sites from DNA sequences. Sci Rep 7:4071
Li, Na; Jang, Hyunbum; Yuan, Ming et al. (2017) Graphite-Templated Amyloid Nanostructures Formed by a Potential Pentapeptide Inhibitor for Alzheimer's Disease: A Combined Study of Real-Time Atomic Force Microscopy and Molecular Dynamics Simulations. Langmuir 33:6647-6656
Zhang, Mingzhen; Zheng, Jie; Nussinov, Ruth et al. (2017) Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane. Sci Rep 7:2635
Xu, Liang; Ma, Buyong; Nussinov, Ruth et al. (2017) Familial Mutations May Switch Conformational Preferences in ?-Synuclein Fibrils. ACS Chem Neurosci 8:837-849
Gan, Wenxun; Schneidman, Dina; Zhang, Ning et al. (2017) Probing Oligomerized Conformations of Defensin in the Membrane. Methods Mol Biol 1529:353-362
Zhao, Jun; Nussinov, Ruth; Ma, Buyong (2017) Allosteric control of antibody-prion recognition through oxidation of a disulfide bond between the CH and CL chains. Protein Eng Des Sel 30:67-76
Onel, Melis; Sumbul, Fidan; Liu, Jin et al. (2017) Cullin neddylation may allosterically tune polyubiquitin chain length and topology. Biochem J 474:781-795
Nussinov, Ruth; Wang, Guanqiao; Tsai, Chung-Jung et al. (2017) Calmodulin and PI3K Signaling in KRAS Cancers. Trends Cancer 3:214-224

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