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Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 April 2018) | Viewed by 43247

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Prof. Dr. Jack A. Tuszynski

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Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
Interests: computational drug design; systems biology of cancer and neurodegenerative diseases; tubulin
Special Issues, Collections and Topics in MDPI journals

Dr. Marco A. Deriu

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Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Galleria 2, CH-6928 Manno, Switzerland
Interests: molecular modeling; computational chemistry; molecular dynamics; molecular dynamics simulation; quantum chemistry; cell mechanics; actin; toll-like receptors; computer aided drug design; microtubule dynamics; Parkinson’s disease; molecular simulation; Alzheimer’s disease; ghrelin receptors; protein–protein interaction; molecular models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, the process of development of a drug molecule is characterized by a huge number of failures, due in large part to inadequate pharmacokinetics, lack of efficacy, toxicity, side effects, etc. In the last few decades molecular modelling has been recognized as a powerful tool helping to shed light on structure-activity relationships, by investigating drug–protein interactions at atomic resolution. Moreover, the availability of thousands of three-dimensional structures of protein offers crucial structural information about key macromolecular drug targets. Starting from drug-target models, the integration of in silico and experimental methods has provided the up-to-date understanding of complex aspects characterizing inter-molecular recognition. For example, flexibility and conformational dynamics of the target is an essential but frequently overlooked aspect in such studies. In fact, receptors may undergo significant local and global structural modifications, following the molecular recognition process, which, subsequently, affects the protein function. Addressing the above-mentioned issues is crucial in evaluating the effect of a binder on the target structure. Computational molecular modelling faces these challenges by employing techniques such as molecular dynamics (MD), which enable quantitative prediction of physical/chemical properties of protein-drug complexes. The emerging enhanced sampling techniques, such as replica exchange MD, metadynamics, simulated annealing and hybrid methods offer improved estimates of the binding free energy by facilitating the system’s escape from conformational traps around local free energy minima. Such computational approaches provide insights into mechanisms of action of drug molecules by exploring both local and non-local effects on protein targets. Hence, they represent a powerful and promising approach aiding in drug discovery and the field of modern medicinal chemistry in general. At present, the research in the area of drug-protein interactions remains an endless source of challenging issues.

This Special Issue will cover latest advances in computational modelling applied to the investigations of physiological and pathological conditions, such as cancer and neurodegenerative diseases. The emphasis will be on: Drug design/screening and molecular docking; classical and enhanced sampling techniques to characterize drug–protein binding, affinity and kinetics; atomistic and coarse-grained approaches to explore local and global effects of drug–protein interactions.

Prof. Dr. Jack A. Tuszynski
Dr. Marco A. Deriu
Guest Editors

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Keywords

Classical/Enhanced molecular/coarse-grained modelling
Drug-protein interactions, free-energy, affinity, kinetics
Drug repurposing, natural compounds, medicinal chemistry
Neurodegenerative disease, cancer
Protein conformational changes
Protein collective motions, modes and Glocal correlations

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Published Papers (8 papers)

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Research

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23 pages, 5203 KiB

Open AccessArticle

Using a Consensus Docking Approach to Predict Adverse Drug Reactions in Combination Drug Therapies for Gulf War Illness

by Rajeev Jaundoo, Jonathan Bohmann, Gloria E. Gutierrez, Nancy Klimas, Gordon Broderick and Travis J. A. Craddock

Int. J. Mol. Sci. 2018, 19(11), 3355; https://doi.org/10.3390/ijms19113355 - 26 Oct 2018

Cited by 18 | Viewed by 3953

Abstract

Gulf War Illness (GWI) is a chronic multisymptom illness characterized by fatigue, musculoskeletal pain, and gastrointestinal and cognitive dysfunction believed to stem from chemical exposures during the 1990–1991 Persian Gulf War. There are currently no treatments; however, previous studies have predicted a putative multi-intervention treatment composed of inhibiting Th1 immune cytokines followed by inhibition of the glucocorticoid receptor (GCR) to treat GWI. These predictions suggest the use of specific monoclonal antibodies or suramin to target interleukin-2 and tumor necrosis factor

α

, followed by mifepristone to inhibit the GCR. In addition to this putative treatment strategy, there exist a variety of medications that target GWI symptomatology. As pharmaceuticals are promiscuous molecules, binding to multiple sites beyond their intended targets, leading to off-target interactions, it is key to ensure that none of these medications interfere with the proposed treatment avenue. Here, we used the drug docking programs AutoDock 4.2, AutoDock Vina, and Schrödinger’s Glide to assess the potential off-target immune and hormone interactions of 43 FDA-approved drugs commonly used to treat GWI symptoms in order to determine their putative polypharmacology and minimize adverse drug effects in a combined pharmaceutical treatment. Several of these FDA-approved drugs were predicted to be novel binders of immune and hormonal targets, suggesting caution for their use in the proposed GWI treatment strategy symptoms. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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17 pages, 3431 KiB

Open AccessArticle

Protein Environment: A Crucial Triggering Factor in Josephin Domain Aggregation: The Role of 2,2,2-Trifluoroethanol

by Cristina Visentin, Susanna Navarro, Gianvito Grasso, Maria Elena Regonesi, Marco Agostino Deriu, Paolo Tortora and Salvador Ventura

Int. J. Mol. Sci. 2018, 19(8), 2151; https://doi.org/10.3390/ijms19082151 - 24 Jul 2018

Cited by 3 | Viewed by 3729

Abstract

The protein ataxin-3 contains a polyglutamine stretch that triggers amyloid aggregation when it is expanded beyond a critical threshold. This results in the onset of the spinocerebellar ataxia type 3. The protein consists of the globular N-terminal Josephin domain and a disordered C-terminal tail where the polyglutamine stretch is located. Expanded ataxin-3 aggregates via a two-stage mechanism: first, Josephin domain self-association, then polyQ fibrillation. This highlights the intrinsic amyloidogenic potential of Josephin domain. Therefore, much effort has been put into investigating its aggregation mechanism(s). A key issue regards the conformational requirements for triggering amyloid aggregation, as it is believed that, generally, misfolding should precede aggregation. Here, we have assayed the effect of 2,2,2-trifluoroethanol, a co-solvent capable of stabilizing secondary structures, especially α-helices. By combining biophysical methods and molecular dynamics, we demonstrated that both secondary and tertiary JD structures are virtually unchanged in the presence of up to 5% 2,2,2-trifluoroethanol. Despite the preservation of JD structure, 1% of 2,2,2-trifluoroethanol suffices to exacerbate the intrinsic aggregation propensity of this domain, by slightly decreasing its conformational stability. These results indicate that in the case of JD, conformational fluctuations might suffice to promote a transition towards an aggregated state without the need for extensive unfolding, and highlights the important role played by the environment on the aggregation of this globular domain. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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9 pages, 1732 KiB

Open AccessArticle

Using Spectral Representation to Classify Proteins’ Conformational States

by Seyed Majid Saberi Fathi and Jack A. Tuszynski

Int. J. Mol. Sci. 2018, 19(7), 2089; https://doi.org/10.3390/ijms19072089 - 18 Jul 2018

Viewed by 2606

Abstract

Numerous proteins are molecular targets for drug action and hence are important in drug discovery. Structure-based computational drug discovery relies on detailed information regarding protein conformations for subsequent drug screening in silico. There are two key issues in analyzing protein conformations in virtual screening. The first considers the protein’s conformational change in response to physical and chemical conditions. The second is the protein’s atomic resolution reconstruction from X-ray crystallography or nuclear magnetic resonance (NMR) data. In this latter problem, information is needed regarding the sample’s position relative to the source of X-rays. Here, we introduce a new measure for classifying protein conformational states using spectral representation and Wigner’s D-functions. Predictions based on the new measure are in good agreement with conformational states of proteins. These results could also be applied to improve conformational alignment of the snapshots given by protein crystallography. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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13 pages, 1916 KiB

Open AccessArticle

A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet β-Cells

by Marie Nicole Bongiovanni, Francesco Antonio Aprile, Pietro Sormanni and Michele Vendruscolo

Int. J. Mol. Sci. 2018, 19(5), 1443; https://doi.org/10.3390/ijms19051443 - 12 May 2018

Cited by 14 | Viewed by 5320

Abstract

Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet β-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the specificity and activity of Hsp70 towards hIAPP, thus providing evidence that the strategy presented here provides a possible route for rationally tailoring molecular chaperones for enhancing their effects in a target-dependent manner. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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13 pages, 2281 KiB

Open AccessArticle

Computational Characterization of Small Molecules Binding to the Human XPF Active Site and Virtual Screening to Identify Potential New DNA Repair Inhibitors Targeting the ERCC1-XPF Endonuclease

by Francesco Gentile, Khaled H. Barakat and Jack A. Tuszynski

Int. J. Mol. Sci. 2018, 19(5), 1328; https://doi.org/10.3390/ijms19051328 - 30 Apr 2018

Cited by 13 | Viewed by 4854

Abstract

The DNA excision repair protein ERCC-1-DNA repair endonuclease XPF (ERCC1-XPF) is a heterodimeric endonuclease essential for the nucleotide excision repair (NER) DNA repair pathway. Although its activity is required to maintain genome integrity in healthy cells, ERCC1-XPF can counteract the effect of DNA-damaging therapies such as platinum-based chemotherapy in cancer cells. Therefore, a promising approach to enhance the effect of these therapies is to combine their use with small molecules, which can inhibit the repair mechanisms in cancer cells. Currently, there are no structures available for the catalytic site of the human ERCC1-XPF, which performs the metal-mediated cleavage of a DNA damaged strand at 5′. We adopted a homology modeling strategy to build a structural model of the human XPF nuclease domain which contained the active site and to extract dominant conformations of the domain using molecular dynamics simulations followed by clustering of the trajectory. We investigated the binding modes of known small molecule inhibitors targeting the active site to build a pharmacophore model. We then performed a virtual screening of the ZINC Is Not Commercial 15 (ZINC15) database to identify new ERCC1-XPF endonuclease inhibitors. Our work provides structural insights regarding the binding mode of small molecules targeting the ERCC1-XPF active site that can be used to rationally optimize such compounds. We also propose a set of new potential DNA repair inhibitors to be considered for combination cancer therapy strategies. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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10 pages, 5067 KiB

Open AccessArticle

Insights into the Impact of Linker Flexibility and Fragment Ionization on the Design of CK2 Allosteric Inhibitors: Comparative Molecular Dynamics Simulation Studies

by Yue Zhou, Na Zhang, Xiaoqian Qi, Shan Tang, Guohui Sun, Lijiao Zhao, Rugang Zhong and Yongzhen Peng

Int. J. Mol. Sci. 2018, 19(1), 111; https://doi.org/10.3390/ijms19010111 - 1 Jan 2018

Cited by 2 | Viewed by 4062

Abstract

Protein kinase is a novel therapeutic target for human diseases. The off-target and side effects of ATP-competitive inhibitors preclude them from the clinically relevant drugs. The compounds targeting the druggable allosteric sites outside the highly conversed ATP binding pocket have been identified as promising alternatives to overcome current barriers of ATP-competitive inhibitors. By simultaneously interacting with the αD region (new allosteric site) and sub-ATP binding pocket, the attractive compound CAM4066 was named as allosteric inhibitor of CK2α. It has been demonstrated that the rigid linker and non-ionizable substituted fragment resulted in significant decreased inhibitory activities of compounds. The molecular dynamics simulations and energy analysis revealed that the appropriate coupling between the linker and pharmacophore fragments were essential for binding of CAM4066 with CK2α. The lower flexible linker of compound 21 lost the capability of coupling fragments A and B to αD region and positive area, respectively, whereas the methyl benzoate of fragment B induced the re-orientated Pre-CAM4066 with the inappropriate polar interactions. Most importantly, the match between the optimized linker and pharmacophore fragments is the challenging work of fragment-linking based drug design. These results provide rational clues to further structural modification and development of highly potent allosteric inhibitors of CK2. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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2727 KiB

Open AccessArticle

Structure and Molecular Dynamics Simulations of Protein Tyrosine Phosphatase Non-Receptor 12 Provide Insights into the Catalytic Mechanism of the Enzyme

by Hui Dong, Francesco Zonta, Shanshan Wang, Ke Song, Xin He, Miaomiao He, Yan Nie and Sheng Li

Int. J. Mol. Sci. 2018, 19(1), 60; https://doi.org/10.3390/ijms19010060 - 26 Dec 2017

Cited by 9 | Viewed by 7492

Abstract

Protein tyrosine phosphatase non-receptor 12 (PTPN12) is an important protein tyrosine phosphatase involved in regulating cell adhesion and migration as well as tumorigenesis. Here, we solved a crystal structure of the native PTPN12 catalytic domain with the catalytic cysteine (residue 231) in dual conformation (phosphorylated and unphosphorylated). Combined with molecular dynamics simulation data, we concluded that those two conformations represent different states of the protein which are realized during the dephosphorylation reaction. Together with docking and mutagenesis data, our results provide a molecular basis for understanding the catalytic mechanism of PTPN12 and its role in tumorigenesis. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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Review

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27 pages, 1823 KiB

Open AccessReview

Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms

by Sofia Giorgetti, Claudio Greco, Paolo Tortora and Francesco Antonio Aprile

Int. J. Mol. Sci. 2018, 19(9), 2677; https://doi.org/10.3390/ijms19092677 - 9 Sep 2018

Cited by 117 | Viewed by 10357

Abstract

Amyloids result from the aggregation of a set of diverse proteins, due to either specific mutations or promoting intra- or extra-cellular conditions. Structurally, they are rich in intermolecular β-sheets and are the causative agents of several diseases, both neurodegenerative and systemic. It is believed that the most toxic species are small aggregates, referred to as oligomers, rather than the final fibrillar assemblies. Their mechanisms of toxicity are mostly mediated by aberrant interactions with the cell membranes, with resulting derangement of membrane-related functions. Much effort is being exerted in the search for natural antiamyloid agents, and/or in the development of synthetic molecules. Actually, it is well documented that the prevention of amyloid aggregation results in several cytoprotective effects. Here, we portray the state of the art in the field. Several natural compounds are effective antiamyloid agents, notably tetracyclines and polyphenols. They are generally non-specific, as documented by their partially overlapping mechanisms and the capability to interfere with the aggregation of several unrelated proteins. Among rationally designed molecules, we mention the prominent examples of β-breakers peptides, whole antibodies and fragments thereof, and the special case of drugs with contrasting transthyretin aggregation. In this framework, we stress the pivotal role of the computational approaches. When combined with biophysical methods, in several cases they have helped clarify in detail the protein/drug modes of interaction, which makes it plausible that more effective drugs will be developed in the future. Full article

(This article belongs to the Special Issue Drug-Protein Interactions and Mechanisms of Action by Structural Modifications Driving Protein Function)

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