scholarly journals Novel method to identify group-specific non-catalytic pockets of human kinome for drug design

RSC Advances ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 2004-2015 ◽  
Author(s):  
Huiwen Wang ◽  
Zeyu Guan ◽  
Jiadi Qiu ◽  
Ya Jia ◽  
Chen Zeng ◽  
...  
Keyword(s):  
Drug Design ◽  
Drug Targets ◽  
Hybrid Approach ◽  
Biological Pathways ◽  
Novel Method ◽  
Human Kinome

Kinase proteins have been intensively investigated as drug targets for decades because of their crucial involvement in many biological pathways. We developed hybrid approach to identify non-catalytic pockets and will benefit the kinome drug design.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

Phytochemicals for drug discovery in Alzheimer’s disease: In silico Advances

2020 ◽  
Vol 26 ◽  
Author(s):  
Smriti Sharma ◽  
Vinayak Bhatia
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Design ◽  
In Silico ◽  
Drug Targets ◽  
Development Process ◽  
Phytochemical Analysis ◽  
Computational Drug Design ◽  
Novel Drugs ◽  
Game Changer

: The search for novel drugs that can prevent or control Alzheimer’s disease has attracted lot of attention from researchers across the globe. Phytochemicals are increasingly being used to provide scaffolds to design drugs for AD. In silico techniques, have proven to be a game-changer in this drug design and development process. In this review, the authors have focussed on current advances in the field of in silico medicine, applied to phytochemicals, to discover novel drugs to prevent or cure AD. After giving a brief context of the etiology and available drug targets for AD, authors have discussed the latest advances and techniques in computational drug design of AD from phytochemicals. Some of the prototypical studies in this area are discussed in detail. In silico phytochemical analysis is a tool of choice for researchers all across the globe and helps integrate chemical biology with drug design.

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.

Techniques to examine nucleotide binding by pseudokinases

2013 ◽  
Vol 41 (4) ◽  
pp. 975-980 ◽  
Author(s):  
Isabelle S. Lucet ◽  
Jeffrey J. Babon ◽  
James M. Murphy
Keyword(s):  
Signal Transduction ◽  
Drug Targets ◽  
Nucleotide Binding ◽  
Biological Functions ◽  
Binding Properties ◽  
Catalytic Activities ◽  
Functional Studies ◽  
Signalling Molecules ◽  
Advantages And Disadvantages ◽  
Human Kinome

Approximately 10% of the human kinome has been classified as pseudokinases due to the absence of one or more of three motifs known to play key roles in the catalytic activities of protein kinases. Structural and functional studies are now emerging, reclassifying this ‘dead’ kinase family as essential signalling molecules that act as crucial modulators of signal transduction. This raises the prospect that pseudokinases may well represent an as-yet-unexplored class of drug targets. However, the extent to which nucleotide binding and catalytic activity contribute to the biological functions of pseudokinases remains an area of great controversy. In the present review, we discuss the advantages and disadvantages of the different methods employed to characterize the nucleotide-binding properties and activity of pseudokinases.

scholarly journals Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

2016 ◽  
Author(s):  
Zheng Zhao ◽  
Lei Xie ◽  
Philip E. Bourne
Keyword(s):  
Molecular Dynamics ◽  
Binding Site ◽  
Protein Kinases ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Allosteric Inhibitors ◽  
Type Iii ◽  
Human Kinome

AbstractProtein kinases are critical drug targets for treating a large variety of human diseases. Type-I and type-II kinase inhibitors frequently exhibit off-target toxicity or lead to mutation acquired resistance. Two highly specific allosteric type-III MEK-targeted drugs, Trametinib and Cobimetinib, offer a new approach. Thus, understanding the binding mechanism of existing type-III kinase inhibitors will provide insights for designing new type-III kinase inhibitors. In this work we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We propose that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors. Our findings will provide new insights into the design of potent and selective kinases inhibitors.Author SummaryHuman protein kinases represent a large protein family relevant to many diseases, especially cancers, and have become important drug targets. However, developing the desired selective kinase-targeted inhibitors remain challenging. Kinase allosteric inhibitors provide that opportunity, but, to date, few have been designed other than MEK inhibitors. To more efficiently develop kinase allosteric inhibitors, we systematically studied the binding mode of the MEK type-III allosteric kinase inhibitors using structural system pharmacology and molecular dynamics approaches. New insights into the binding mode and mechanism of type-III inhibitors were revealed that may facilitate the design of new prospective type-III kinase inhibitors.

scholarly journals A Novel Method for Technology Forecasting and Developing R&D Strategy of Building Integrated Photovoltaic Technology Industry

2012 ◽  
Vol 2012 ◽  
pp. 1-24 ◽  
Author(s):  
Yu-Jing Chiu ◽  
Tao-Ming Ying
Keyword(s):  
Life Cycle ◽  
Hybrid Approach ◽  
Three Dimensional ◽  
Logistic Growth ◽  
Technology Industry ◽  
Energy Technologies ◽  
Building Integrated Photovoltaic ◽  
Important Trend ◽  
Novel Method ◽  
Map Analysis

Because of global warming, renewable energy technologies have become more essential currently, with solar energy technology advancing worldwide. Therefore, interdisciplinary integration is an important trend, and building-integrated photovoltaic (BIPV) is an emerging technology involving the photovoltaic and building fields. The purpose of this study is to understand the technology evolution of BIPV and to determine the R&D planning direction. This paper proposes a hybrid approach to explore the life cycle of BIPV technology and develop the R&D strategy of related industries. The proposed approach comprises the following submodules. First, patent analysis is employed to transform patent documents into structured data. Second, the logistic growth model is used to explore the life cycle of BIPV technology. Third, a patent matrix map analysis is used to develop the R&D strategy of the BIPV industry. Through the analysis by the logistic model, the BIPV technology is transformed from the emerging stage to the growth stage of a long-term life cycle. The other important result is created by the three-dimensional matrix for R&D strategies in this paper.

scholarly journals Targeting comorbid diseases via network endopharmacology

2018 ◽  
Author(s):  
Juaquim Aguirre-Plans ◽  
Janet Piñero ◽  
Jörg Menche ◽  
Ferran Sanz ◽  
Laura I Furlong ◽  
...  
Keyword(s):  
Drug Targets ◽  
Natural Extension ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Biological Pathways ◽  
Pathway Enrichment Analysis ◽  
Disease Genes ◽  
Multiple Targets ◽  
Clear Cut ◽  
Traditional Drug

AbstractThe traditional drug discovery paradigm has shaped around the idea of “one target, one disease”. Recently, it has become clear that not only it is hard to achieve single target specificity but also it is often more desirable to tinker the complex cellular network by targeting multiple proteins, causing a paradigm shift towards polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is targeting common biological pathways involved in diseases, giving rise to “endopharmacology” (multiple targets, multiple diseases). In this study, leveraging powerful network medicine tools, we describe a recipe for first, identifying common pathways pertaining to diseases and then, prioritizing drugs that target these pathways towards endopharmacology. We present proximal pathway enrichment analysis (PxEA) that uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs for their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. As a proof of principle, we focus on nine autoimmune disorders and using PxEA, we show that many drugs indicated for these conditions are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide the high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two phenotypes that have recently gained attention due to the increased comorbidity among patients.

scholarly journals Advances toward structure-based drug discovery for inflammasome targets

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Li Wang ◽  
Michael A. Crackower ◽  
Hao Wu
Keyword(s):  
Drug Discovery ◽  
High Resolution ◽  
Drug Design ◽  
Structural Biology ◽  
Drug Targets ◽  
Unmet Need ◽  
Structure Based Drug Design ◽  
Important Family ◽  
Recent Advances

Inflammasome proteins play an important role in many diseases of high unmet need, making them attractive drug targets. However, drug discovery for inflammasome proteins has been challenging in part due to the difficulty in solving high-resolution structures using cryo-EM or crystallography. Recent advances in the structural biology of NLRP3 and NLRP1 have provided the first set of data that proves a promise for structure-based drug design for this important family of targets.

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