ABSTRACT
The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease. To identify these molecules, we followed a combinatorial structure-based strategy, which includes high-throughput virtual screening, molecular docking and WaterMap calculations. The study was carried out using Protein Data Bank structures 5R82 and 6Y2G. DrugBank, Enamine, Natural product and Specs databases, along with a few known antiviral drugs, were used for the screening. WaterMap analysis aided in the recognition of high-potential molecules that can efficiently displace binding-site waters. This study may help the discovery and development of antiviral drugs against SARS-CoV-2.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Binding Sites/drug effects , Catalysis , Computer Simulation , Databases, Factual , High-Throughput Screening Assays , Humans , Molecular Docking Simulation , Molecular Structure , Protease Inhibitors/pharmacokinetics , Thermodynamics , Water/chemistryABSTRACT
INTRODUCTION: Protein kinase C (PKC) comprises at least 10 isoforms, pivotal in various cellular differentiation processes and in other specific cellular functions. Catalytic subunits of all PKCs are highly conserved which play a central role in the development of kinase-specific inhibitors for the treatment of a number of diseases and also in the drug resistance and immunological disorders. The authors' previous work of reviewing patents of PKC inhibitors is continued in this report. AREA COVERED: Thorough survey on the physiological roles of PKC isoforms and patents filed for PKC inhibitors from 2010 to present representing new and potential strategy for the cure and prevention of disorders due to elevation in various PKC levels is reported. EXPERT OPINION: The PKC isoforms are unique in terms of tissue distribution and an elevation in any isoform level results in different diseased conditions. Different PKC isoforms have high sequence identity but they are involved in different diseases. Crystal structure of few PKC isoforms viz. C1 domain of PKCδ, the C2 domains of PKCα and ß, kinase domain and full structure of PKCßII are known. Identification of more crystal structures and thorough analysis of available structures and information on the PKC ligands will be helpful in the drug designing and development processes.
Subject(s)
Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Alzheimer Disease/drug therapy , Animals , Diabetes Complications/drug therapy , Humans , Isoenzymes/chemistry , Ligands , Neoplasms/drug therapy , Patents as Topic , Signal Transduction/drug effects , Tissue DistributionABSTRACT
INTRODUCTION: The protein kinase C (PKC) is a family of multifunctional isoenzymes involved in apoptosis, migration, adhesion, tumorgenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation. It also plays a vital role in the regulation of signal transduction, cell proliferation and differentiation through positive and negative regulation of the cell cycle. In this work, we reviewed the existing PKC inhibitors and several patents linked to PKC inhibitors. AREAS COVERED: Thorough survey on the PKC inhibitors having clinical importance and patents filed for these inhibitors from 2008 - 2009 is reported. EXPERT OPINION: PKCs are highly potential therapeutic targets for treating diabetic complications, oncological, inflammatory, immunological and dermatological disorders. The clinical trial candidates of PKCs mainly target the catalytic domain, which is highly conserved throughout the PKC family making it difficult to target a particular isoform selectively. Relatively less chemical space and fewer bisubstrate inhibitors targeting both ATP and regulatory domain are explored for PKCs, more research in these areas will be helpful in overcoming existing problems.
Subject(s)
Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Drug Design , Drug Discovery , Humans , Isoenzymes/antagonists & inhibitors , Patents as Topic , Protein Kinase Inhibitors/classification , Protein Kinase Inhibitors/therapeutic useABSTRACT
INTRODUCTION: The protein tyrosine phosphatases (PTPases or PTPs) are highly conserved phosphatases that regulate the tyrosine phosphorylation and consequently, the cellular functions. Protein tyrosine phosphorylation is the major post-translational modification to regulate signal transduction in cells. PTPs control diverse processes such as focal adhesion dynamics, cell-cell adhesion, insulin signaling, cytoskeletal functions, synaptogenesis and neurite growth. The availability of numerous X-ray crystal structures of PTPs, along with their inhibitors, has provided the opportunity for the structure-based design of effective inhibitors having potential for the treatment of various disorders. AREAS COVERED: The main focus of the present review is to get an insight into the most clinically relevant therapeutic PTP inhibitors published in patents over the past 10 years. EXPERT OPINION: Several computational studies are being carried out to understand ligand binding modes, selectivity interactions and conformational changes during inhibitor binding. PTP inhibitors that are of current interest include quinolyl, cyclic alabenzimidazole, pyrazine, (ethynediyl)bis-benzene, pyridopyrimidine, triazolopyridine, cyclo propylphenyl phenyloxamides, oxindole and azoloarin derivatives. The development of allosteric site-directed PTP inhibitors may help in understanding the absorption and selectivity of PTP inhibitors.
