Advance in L-Type Calcium Channel Structures, Functions and Molecular Modeling

2020 ◽  
Vol 27 ◽  
Author(s):  
Lei Xu ◽  
Lilei Sun ◽  
Liangxu Xie ◽  
Shanzhi Mou ◽  
Dawei Zhang ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Calcium Channels ◽  
Drug Targets ◽  
Wide Spectrum ◽  
Critical Role ◽  
Muscular Contraction ◽  
Physiological Processes ◽  
Ligand Binding Sites ◽  
Channel Structures ◽  
Important Drug

: L-type calcium channels (LTCCs), also termed as Cav1, belong to voltage-gated calcium channels (VGCCs/Cavs), which play a critical role in a wide spectrum of physiological processes, including neurotransmission, cell cycle, muscular contraction, cardiac action potential and gene expression. Aberrant regulation of calcium channels is involved in neurological, cardiovascular, muscular and psychiatric disorders. Accordingly, LTCCs have been regarded as important drug targets, and a number of LTCC drugs are in clinical use. In this review, the recent development of structures and biological functions of LTCCs are introduced. Moreover, the representative modulators and ligand binding sites of LTCCs are discussed. Finally, molecular modeling and computer-aided drug design (CADD) methods for understanding structure-function relations of LTCCs are summarized.

scholarly journals Detect Genomic G-Quadruplexes in Living Animal Cells with a Tiny Artificial Protein Probe

2020 ◽  
Author(s):  
Ke-wei Zheng ◽  
Jia-yu Zhang ◽  
Yi-de He ◽  
Jia-yuan Gong ◽  
Cui-jiao Wen ◽  
...  
Keyword(s):  
Drug Targets ◽  
Fold Increase ◽  
Molecular Devices ◽  
Animal Cells ◽  
Physiological Processes ◽  
Genome Wide ◽  
G Quadruplex ◽  
Artificial Protein ◽  
Important Drug

ABSTRACTG-quadruplex (G4) structures formed by guanine-rich nucleic acids are implicated in essential physiological processes and serve as important drug targets. The genome-wide detection of G4s in living cells is important for exploring the biological role of G4s but has not yet been achieved due to the lack of a suitable G4 probe. We engineered a 6.7 kDa G4 probe (G4P) protein that binds G4s with high affinity and specificity. We used it to capture G4s in living human, mouse, and chicken cells with the ChIP-Seq technology, yielding genome-wide landscape as well as details on the positions, frequencies, and sequence identities of G4 formation in these cells. Our results indicate that transcription is accompanied by a robust formation of G4s in genes. In human cells, we detected up to >123,000 G4 peaks, of which >1/3 had a fold increase of ≥5 and were present in >60% promoters and ~70% genes. Being much smaller than a scFv antibody (27 kDa) or even a nanobody (12-15 kDa), we expect that the G4P may find diverse applications in biology, medicine, and molecular devices as a G4 affinity agent.

scholarly journals Identification of novel small molecule inhibitors against nsP2 protease of CHIKV through a molecular modeling approach

2021 ◽  
Author(s):  
Sutanu Mukhopadhyay
Keyword(s):  
Molecular Modeling ◽  
Active Site ◽  
Drug Targets ◽  
Experimental Validation ◽  
De Novo ◽  
Viral Disease ◽  
Disease Spread ◽  
Structural Protein ◽  
Potential Inhibitors ◽  
Important Drug

Abstract Chikungunya is a tropical viral disease spread by the female Aedes mosquitoes infected with the Chikungunya virus (CHIKV). Non-structural protein 2 (nsp2) plays a crucial role in the viral life cycle by its proteolytic activity and hence it is one of the most important drug targets. There is currently no permanent treatment available to tackle the infection. In this molecular modeling-based study, a combination of de novo ligand design, molecular docking, and ADMET-based screening is employed to identify novel inhibitor molecules targeting the active site of nsP2 protease of the CHIKV. A set of molecules have been shortlisted as potential inhibitors based on their binding affinity and drug-likeness score. Further experimental validation is required to verify the potency of the proposed leads against CHIKV nsp2 protease activity to combat the infection.

scholarly journals Neuronal and Cardiovascular Potassium Channels as Therapeutic Drug Targets

2015 ◽  
Vol 20 (9) ◽  
pp. 1055-1073 ◽  
Author(s):  
Edward S. A. Humphries ◽  
Caroline Dart
Keyword(s):  
Drug Targets ◽  
Therapeutic Strategy ◽  
Genetic Disorders ◽  
Critical Role ◽  
Therapeutic Drug ◽  
Cellular Excitability ◽  
Human Genetic Disorders ◽  
The Brain ◽  
Important Drug

Potassium (K+) channels, with their diversity, often tissue-defined distribution, and critical role in controlling cellular excitability, have long held promise of being important drug targets for the treatment of dysrhythmias in the heart and abnormal neuronal activity within the brain. With the exception of drugs that target one particular class, ATP-sensitive K+ (KATP) channels, very few selective K+ channel activators or inhibitors are currently licensed for clinical use in cardiovascular and neurological disease. Here we review what a range of human genetic disorders have told us about the role of specific K+ channel subunits, explore the potential of activators and inhibitors of specific channel populations as a therapeutic strategy, and discuss possible reasons for the difficulty in designing clinically relevant K+ channel modulators.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

scholarly journals PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Metabolic Regulation ◽  
Structural Changes ◽  
Critical Role ◽  
The Body ◽  
Molecular Characteristics ◽  
Signal Pathways ◽  
Virus Infections ◽  
Physiological Processes ◽  
Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

scholarly journals Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 821
Author(s):  
Wanglong Qiu ◽  
Chia-Yu Kuo ◽  
Yu Tian ◽  
Gloria H. Su
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Critical Role ◽  
Genetic Mutations ◽  
Cancer Genetic ◽  
Dual Roles ◽  
Activin Signaling ◽  
Physiological Processes ◽  
Cancer Types ◽  
Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

Molecular modulation of calcium oxalate crystallization

2006 ◽  
Vol 291 (6) ◽  
pp. F1123-F1132 ◽  
Author(s):  
James J. De Yoreo ◽  
S. Roger Qiu ◽  
John R. Hoyer
Keyword(s):  
Molecular Modeling ◽  
Calcium Oxalate ◽  
Stone Formation ◽  
Energy Levels ◽  
Critical Role ◽  
Specific Interactions ◽  
Crystal Surfaces ◽  
Site Specific

Calcium oxalate monohydrate (COM) is the primary constituent of the majority of renal stones. Osteopontin (OPN), an aspartic acid-rich urinary protein, and citrate, a much smaller molecule, are potent inhibitors of COM crystallization at levels present in normal urine. Current concepts of the role of site-specific interactions in crystallization derived from studies of biomineralization are reviewed to provide a context for understanding modulation of COM growth at a molecular level. Results from in situ atomic force microscopy (AFM) analyses of the effects of citrate and OPN on growth verified the critical role of site-specific interactions between these growth modulators and individual steps on COM crystal surfaces. Molecular modeling investigations of interactions of citrate with steps and faces on COM crystal surfaces provided links between the stereochemistry of interaction and the binding energy levels that underlie mechanisms of growth modification and changes in overall crystal morphology. The combination of in situ AFM and molecular modeling provides new knowledge that will aid rationale design of therapeutic agents for inhibition of stone formation.

Critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice

Toxicology ◽  
2019 ◽  
Vol 413 ◽  
pp. 33-39 ◽  
Author(s):  
Shiori Tomita ◽  
Fumiko Sekiguchi ◽  
Tomoyo Deguchi ◽  
Takaya Miyazaki ◽  
Yuya Ikeda ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Calcium Channels ◽  
Chemotherapeutic Agent ◽  
Critical Role

scholarly journals In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2551 ◽  
Author(s):  
Sathyadevi Palanisamy ◽  
Yu-Liang Wang ◽  
Yu-Jen Chen ◽  
Chiao-Yun Chen ◽  
Fu-Te Tsai ◽  
...  
Keyword(s):  
Critical Role ◽  
Model Organism ◽  
Living Cells ◽  
Biological Species ◽  
Zebrafish Model ◽  
Physiological Processes ◽  
Collective Data ◽  
Angeli's Salt

Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli’s salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40–360 µM with a detection limit of 9.05 µM. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.

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