scholarly journals Predicting the Specificity-Determining Positions of Paralogous Complexes

2021 ◽  
Author(s):  
Tülay Karakulak ◽  
Ahmet Sureyya Rifaioglu ◽  
João P.G.L.M. Rodrigues ◽  
Ezgi Karaca
Keyword(s):  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Protein Complexes ◽  
Critical Study ◽  
Sequence Structure ◽  
Comparative Performance ◽  
Specificity Determining Positions ◽  
Different Types ◽  
Therapeutic Molecules ◽  
Dynamics Simulations

ABSTRACTDue to its clinical relevance, modulation of functionally relevant amino acids in protein-protein complexes has attracted a great deal of attention. To this end, many approaches have been proposed to predict partner-selecting, i.e., specificity-determining positions in evolutionarily close complexes. These approaches can be grouped into sequence-based machine learning and structure-based energy-driven methods. In this work, we assessed these methods’ ability to map the specificity-determining positions of Axl, a receptor tyrosine kinase involved in cancer progression and immune-related diseases. For this, we used three sequence-based predictors – SDPred, Multi-RELIEF, and Sequence Harmony – and a structure-based approach by utilizing HADDOCK and extensive molecular dynamics simulations. As a result, we show that (i) sequence-based methods overpredict the number of specificity-determining positions for Axl complexes and that (ii) combining sequence-based approaches with HADDOCK provides the most coherent set of predictions. Our work lays out a critical study on the comparative performance specificity-determining position predictors. It also presents a combined sequence-structure-based approach, which can guide the development of therapeutic molecules capable of combatting Axl misregulation in different types of diseases.

scholarly journals Predicting the Specificity- Determining Positions of Receptor Tyrosine Kinase Axl

2021 ◽  
Vol 8 ◽  
Author(s):  
Tülay Karakulak ◽  
Ahmet Sureyya Rifaioglu ◽  
João P. G. L. M. Rodrigues ◽  
Ezgi Karaca
Keyword(s):  
Molecular Dynamics ◽  
Tyrosine Kinase ◽  
Molecular Dynamics Simulations ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Protein Complexes ◽  
Immune System Diseases ◽  
Specificity Determining Positions ◽  
Therapeutic Molecules ◽  
Dynamics Simulations

Owing to its clinical significance, modulation of functionally relevant amino acids in protein-protein complexes has attracted a great deal of attention. To this end, many approaches have been proposed to predict the partner-selecting amino acid positions in evolutionarily close complexes. These approaches can be grouped into sequence-based machine learning and structure-based energy-driven methods. In this work, we assessed these methods’ ability to map the specificity-determining positions of Axl, a receptor tyrosine kinase involved in cancer progression and immune system diseases. For sequence-based predictions, we used SDPpred, Multi-RELIEF, and Sequence Harmony. For structure-based predictions, we utilized HADDOCK refinement and molecular dynamics simulations. As a result, we observed that (i) sequence-based methods overpredict partner-selecting residues of Axl and that (ii) combining Multi-RELIEF with HADDOCK-based predictions provides the key Axl residues, covered by the extensive molecular dynamics simulations. Expanding on these results, we propose that a sequence-structure-based approach is necessary to determine specificity-determining positions of Axl, which can guide the development of therapeutic molecules to combat Axl misregulation.

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

2020 ◽  
Vol 20 (6) ◽  
pp. 444-465 ◽  
Author(s):  
Jessica Ceramella ◽  
Domenico Iacopetta ◽  
Alexia Barbarossa ◽  
Anna Caruso ◽  
Fedora Grande ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Drug Targets ◽  
Mechanisms Of Action ◽  
Biological Pathways ◽  
G Protein Coupled Receptors ◽  
Ability To Act ◽  
Different Types ◽  
Activity Of Enzymes ◽  
Intercalating Agents ◽  
G Protein Coupled

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

scholarly journals Application of Cryo-Electron Microscopy on Drug Discovery

2021 ◽  
Vol 27 (S1) ◽  
pp. 3250-3250
Author(s):  
Viswanath Vittaladevaram ◽  
Kranthi Kuruti
Keyword(s):  
Electron Microscopy ◽  
Protein Complexes ◽  
Lead Discovery ◽  
Biologically Relevant ◽  
Biological Targets ◽  
3 Dimensional ◽  
Drug Molecules ◽  
Cryo Electron Microscopy ◽  
Therapeutic Molecules ◽  
Novel Drug

AbstractThe key aspect for development of novel drug molecules is to perform structural determination of target molecule associated with its ligand. One such tool that provides insights towards structure of molecule is Cryo-electron microscopy which covers biological targets that are intractable. Examination of proteins can be carried out in native state, as the samples are frozen at -175 degree Celsius i.e. cryogenic temperatures. In addition to this, there were no limits for molecular and functional structures of proteins that can be imagined in 3-dimensional form. This includes ligands which unravel mechanisms that are biologically relevant. This will enable to better understand the mechanisms that are used for development of new therapeutics. Application of Cryo-electron microscopy is not limited to protein complexes and is considered as non-specific. Intervention of Cryo-EM would allow to analyse the structures and also able to dissect the interaction with therapeutic molecules. The study determines the usage of cryo-EM for providing resolutions that are acceptable for lead discovery. It also provides support for lead optimization and also for discovery of vaccines and therapeutics.

scholarly journals Structural insights into the modulation of PDGF/PDGFR-β complexation by hyaluronan derivatives

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Kanagasabai Balamurugan ◽  
Linda Koehler ◽  
Jan-Niklas Dürig ◽  
Ute Hempel ◽  
Jörg Rademann ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Computational Analysis ◽  
Vascular Endothelial ◽  
Receptor Recognition ◽  
Dynamics Simulations ◽  
Endothelial Growth Factor ◽  
Structural Insights ◽  
Important Physiological Process ◽  
Computational Predictions

Abstract Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.

scholarly journals Lysyl Oxidase Mechanisms to Mediate Gastrointestinal Cancer Progression

2020 ◽  
pp. 1-10
Author(s):  
Ahmadshah Farhat ◽  
Gordon A. Ferns ◽  
Korosh Ashrafi ◽  
Mohammad-Hassan Arjmand
Keyword(s):  
Cancer Progression ◽  
Extracellular Enzymes ◽  
Lysyl Oxidase ◽  
Ecm Remodeling ◽  
Complex Process ◽  
High Prevalence ◽  
Different Types ◽  
Fibrotic Diseases ◽  
Gi Cancers ◽  
Improvement In Survival

<b><i>Background:</i></b> Malignancy is a complex process resulting from different changes such as extracellular matrix (ECM) remodeling and stiffness. One of the important enzymes that contribute to ECM remodeling is lysyl oxidase (Lox) that is overexpressed in different types of human cancers. Because of the high prevalence and poor survival of gastrointestinal (GI) malignancies in this review, we discuss the association between Lox activity and the progression of GI cancers. Lox proteins are a group of extracellular enzymes that catalyzed the cross-linking of collagen and elastin, so they have important roles in the control of structure and homeostasis of ECM. Abnormal activation and expression of the Lox family of proteins lead to changes in the ECM toward increased rigidity and fibrosis. Stiffness of ECM can contribute to the pathogenesis of cancers. <b><i>Summary:</i></b> Dysregulation of Lox expression is a factor in both fibrotic diseases and cancer. ECM stiffness by Lox overactivity creates a physical barrier against intratumoral concentration of chemotherapeutic drugs and facilitates cancer inflammation, angiogenesis, and metastasis. <b><i>Key Message:</i></b> Because of the roles of Lox in GI cancers, development targeting Lox protein isotypes may be an appropriate strategy for treatment of GI cancers and improvement in survival of patients.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

scholarly journals Delivery of cancer therapies by synthetic and bio-inspired nanovectors

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Tina Briolay ◽  
Tacien Petithomme ◽  
Morgane Fouet ◽  
Nelly Nguyen-Pham ◽  
Christophe Blanquart ◽  
...  
Keyword(s):  
Recent Literature ◽  
Biological Properties ◽  
Engineered Nanoparticles ◽  
Oncolytic Viruses ◽  
Cancer Therapies ◽  
Different Types ◽  
Therapeutic Molecules ◽  
Tumor Specificity ◽  
Smart Drug ◽  
Smart Drug Delivery

Abstract Background As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. Main Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of ‘smart’ drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy. Conclusion This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting “type” for efficient and specific delivery of diverse anticancer therapies.

scholarly journals Current Analytical Strategies in Studying Chromatin-Associated-Proteome (Chromatome)

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6694
Author(s):  
Niamat Khan ◽  
Sidra Shahid ◽  
Abdul R. Asif
Keyword(s):  
Drug Targets ◽  
Protein Complexes ◽  
Dynamic Structure ◽  
Associated Diseases ◽  
Specific Complex ◽  
Analytical Strategies ◽  
Associated Proteins ◽  
Therapeutic Molecules ◽  
Unique Nature ◽  
Mass Spectrometric Identification

Chromatin is a dynamic structure comprising of DNA and proteins. Its unique nature not only help to pack the DNA tightly within the cell but also is pivotal in regulating gene expression DNA replication. Furthermore it also protects the DNA from being damaged. Various proteins are involved in making a specific complex within a chromatin and the knowledge about these interacting partners is helpful to enhance our understanding about the pathophysiology of various chromatin associated diseases. Moreover, it could also help us to identify new drug targets and design more effective remedies. Due to the existence of chromatin in different forms under various physiological conditions it is hard to develop a single strategy to study chromatin associated proteins under all conditions. In our current review, we tried to provide an overview and comparative analysis of the strategies currently adopted to capture the DNA bounded protein complexes and their mass spectrometric identification and quantification. Precise information about the protein partners and their function in the DNA-protein complexes is crucial to design new and more effective therapeutic molecules against chromatin associated diseases.

scholarly journals Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiexia Wen ◽  
Bin Xuan ◽  
Yang Liu ◽  
Liwei Wang ◽  
Li He ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Immune Defense ◽  
Innate Immune ◽  
Sensor Protein ◽  
Different Types ◽  
Microbial Infections ◽  
Activation Mechanisms ◽  
Specific Protease

Inflammasomes comprise a family of cytosolic multi-protein complexes that modulate the activation of cysteine-aspartate-specific protease 1 (caspase-1) and promote the maturation and secretion of interleukin (IL)-1β and IL-18, leading to an inflammatory response. Different types of inflammasomes are defined by their sensor protein which recognizes pathogenic ligands and then directs inflammasome assembly. Although the specific molecular mechanisms underlying the activation of most inflammasomes are still unclear, NLRC4 inflammasomes have emerged as multifaceted agents of the innate immune response, playing important roles in immune defense against a variety of pathogens. Other studies have also expanded the scope of NLRC4 inflammasomes to include a range of inherited human autoimmune diseases as well as proposed roles in cancer. In this review article, we provide an updated overview of NLRC4 inflammasomes, describing their composition, activation mechanisms and roles in both microbial infections and other disease conditions.

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