Proteome wide screening for identification of putative drug target gene in Nautella italica and structure-based ligand screening for therapeutic candidates

2021 ◽  
Vol 25 (12) ◽  
pp. 122-136
Author(s):  
Odumpatta Rajasree ◽  
Arumugam Mohanapriya
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Three Dimensional ◽  
Opportunistic Pathogen ◽  
Dimensional Structure ◽  
Therapeutic Drug ◽  
Zinc Database ◽  
Delisea Pulchra ◽  
Toxicity Analysis ◽  
Potential Ligand

In silico based subtractive genomic approaches were employed to identify the key drug targets for an opportunistic pathogen Nautella italica, a member of the marine Roseobacter clade that causes bleaching disease in the temperate-marine red macro algae, Delisea pulchra. The aim of this study is to propose new active ligands against bleaching disease seen in algae. Using comparative and subtractive genomic approach, a set of 21 proteins were identified as the therapeutic drug target proteins for algal bleaching. This core set of drug targets has been analyzed for network topology using string network analysis and major hub gene identified by CytoHubba was rpoB (DNA directed RNA Polymerase subunit beta). The three-dimensional structure of rpoB was built by comparative modelling and used to perform a virtual screening of Zinc database by DOCK Blaster server. The 50 top scored compounds were screened for toxicity analysis by OSIRIS Data Warrior and ECOSAR tool. Further refinement by autodock program revealed two compounds ZINC49821385 and ZINC97218938 with the best binding energy of -7.07 and -6.79 respectively. These results indicated that 5-(4- isopropylphenyl)furan-2-carboxamide (ZINC ID 49821385) could be one of the potential ligand to treat bleaching disease in algae.

scholarly journals Viral Genome Conformations and Contacts across Different Lifecycle Stages

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 109
Author(s):  
Peter G. Stockley ◽  
Nikesh Patel ◽  
Emma L. Wroblewski ◽  
Andrew J. P. Scott ◽  
Carlos P. Mata ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Drug Targets ◽  
Three Dimensional ◽  
Host Cells ◽  
Dimensional Structure ◽  
Viral Genomes ◽  
Starting Point ◽  
B Virus ◽  
Infection Mechanisms ◽  
Conformational Memory

Single-stranded RNA viral genomes (gRNA) are dynamic molecules that permit packaging into virions and their subsequent extrusion during infection. For viruses with such genomes, we discovered a previously unsuspected mechanism that regulates their assembly. This regulation is the result of multiple cognate coat protein (CP)–gRNA contacts distributed across the RNA. Collectively, these interactions make the assembly highly efficient and specific. The regions of the gRNA packaging signals (PSs) driving this assembly are potential drug targets, whilst the manipulation of PS–CP contacts with nonviral RNA cargos is a route towards bespoke virus-like particles. Infectivity depends on the virions being able to transfer their gRNAs into host cells. The starting point for this transfer appears to be an encapsidated RNA with a defined three-dimensional structure, especially around the PSs. A combination of asymmetric cryo-electron microscopy structure determination and X-ray synchrotron footprinting were used to define these contacts and structures in a number of viral examples, including hepatitis B virus and enteroviruses. These tools allow us to look beyond the outer CP layer of the virion shell and to see the functional, asymmetric components that regulate viral infectivity. This revealed yet more unexpected aspects of critical infection mechanisms, such as the RNA conformational changes required for encapsidation, the details of PS–CP contacts regulating the assembly, and the conformational “memory” imposed by encapsidation.

scholarly journals Structural Analysis of Experimental Drugs Binding to the COVID-19 Target TMPRSS2

2020 ◽  
Author(s):  
David Huggins
Keyword(s):  
Serine Proteases ◽  
Drug Targets ◽  
Three Dimensional ◽  
Life Cycles ◽  
Dimensional Structure ◽  
Experimental Drugs ◽  
Type Plasminogen Activator ◽  
Human Proteins ◽  
Approved Drugs ◽  
New Treatments

<p>The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1’ subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that many serine protease inhibitors may not inhibit TMPRSS2, this is likely to provide a handle for selective targeting. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses. </p><div><br></div>

scholarly journals Structural insights into the substrate specificity of SP_0149, the substrate-binding protein of a methionine ABC transporter from Streptococcus pneumoniae

2019 ◽  
Vol 75 (7) ◽  
pp. 520-528
Author(s):  
Bhavya Jha ◽  
Rajan Vyas ◽  
Jaya Bhushan ◽  
Devinder Sehgal ◽  
Bichitra Kumar Biswal
Keyword(s):  
Streptococcus Pneumoniae ◽  
Substrate Specificity ◽  
Rational Design ◽  
Binding Protein ◽  
Substrate Binding ◽  
Three Dimensional ◽  
Cumulative Effect ◽  
Opportunistic Pathogen ◽  
Dimensional Structure ◽  
Substrate Binding Protein

Successful pathogenesis is a cumulative effect of the virulence factors of a pathogen and its capability to efficiently utilize the available nutrients from the host. Streptococcus pneumoniae, a Gram-positive opportunistic pathogen, may either reside asymptomatically as a nasopharyngeal commensal inside the human host or cause lethal diseases, including pneumonia, meningitis and sepsis. S. pneumoniae is known to acquire methionine (Met) from its host through a Met importer. Here, the crystal structure of the substrate-binding protein (SBP; SP_0149) of an ABC importer with Met bound is reported at a resolution of 1.95 Å. The three-dimensional structure of SBP shows that it is composed of two distinct domains, each consisting of a mixed β-sheet flanked by helices. The substrate, Met, is bound in the central part of the interface between the two domains. The overall structure of SP_0149 resembles those of SBPs from other reported bacterial Met and Gly-Met dipeptide transporters. However, a detailed analysis of these structures shows notable variations in the amino-acid composition of the substrate-binding pockets of the SP_0149–Met and GmpC–Gly-Met structures. In particular, SP_0149 harbors Thr212 and Tyr114, whereas the corresponding residues in GmpC are Gly and Val. This difference is likely to be the underlying basis for their differential substrate specificity. In summary, the structure of the SP_0149–Met complex provides insights into the transport function of SP_0149 and its interactions with methionine. It opens up avenues for the rational design of inhibitors of SP_0149 through a structure-mediated approach.

scholarly journals Structural Analysis of Experimental Drugs Binding to the COVID-19 Target TMPRSS2

2020 ◽  
Author(s):  
David Huggins
Keyword(s):  
Serine Proteases ◽  
Drug Targets ◽  
Three Dimensional ◽  
Life Cycles ◽  
Dimensional Structure ◽  
Experimental Drugs ◽  
Type Plasminogen Activator ◽  
Human Proteins ◽  
Approved Drugs ◽  
New Treatments

<p>The emergence of SARS-CoV-2 has prompted a worldwide health emergency. There is an urgent need for therapeutics, both through the repurposing of approved drugs and the development of new treatments. In addition to the viral drug targets, a number of human drug targets have been suggested. In theory, targeting human proteins should provide an advantage over targeting viral proteins in terms of drug resistance, which is commonly a problem in treating RNA viruses. This paper focuses on the human protein TMPRSS2, which supports coronavirus life cycles by cleaving viral spike proteins. The three-dimensional structure of TMPRSS2 is not known and so we have generated models of the TMPRSS2 in the apo state as well as in complex with a peptide substrate and putative inhibitors to aid future work. Importantly, many related human proteases have 80% or higher identity with TMPRSS2 in the S1-S1’ subsites, with plasminogen and urokinase-type plasminogen activator (uPA) having 95% identity. We highlight 376 approved, investigational or experimental drugs targeting S1A serine proteases that may inhibit TMPRSS2. Whilst the presence of a relatively uncommon lysine residue in the S2/S3 subsites means that many serine protease inhibitors may not inhibit TMPRSS2, this is likely to provide a handle for selective targeting. We discuss how experimental drugs targeting related serine proteases might be repurposed as TMPRSS2 inhibitors to treat coronaviruses. </p><div><br></div>

scholarly journals In Silico Screening of Some Antiviral Phytochemicals as Drug Leads Against Covid-19

2020 ◽  
Author(s):  
Monjur Ahmed Laskar ◽  
Moriom Begam ◽  
Manabendra Dutta Choudhury
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Three Dimensional ◽  
Data Bank ◽  
Drug Candidate ◽  
Present Observation ◽  
Health It ◽  
Main Protease ◽  
And Control ◽  
Drug Leads

<p>Background: COVID-19 caused by SARS-CoV-2 in December 2019 has become a pandemic</p><p>hazard to the community health. It is a respiratory difficulty causing fever, dry cough, fatigue,</p><p>shortness of breath, muscle aches and some instances lead to pneumonia. Coronaviruses have</p><p>large viral RNA Genomes and are single-stranded positive-sense RNA viruses. The nsp10/nsp16</p><p>protein is an important target because it is essential for the virus to replicate, the papain-like</p><p>protease (Nsp3), the main protease (Nsp5), the primary RNA-dependent RNA polymerase</p><p>(Nsp12) are also attractive drug targets for this disease. The uses of phytochemicals as</p><p>therapeutic agents have been increasing in recent years. Some antiviral phytochemicals were</p><p>taken based on literature survey for this study.</p><p>Methods: ADME parameters and drug like nature of phytochemicals were screened using</p><p>SwissADME web tool. Three dimensional structures of targets are downloaded from Protein</p><p>Data Bank and docked with phytochemicals & control by using software FlexX.</p><p>Results: Morin shows significant results in ADME screening and Drug likeness prediction</p><p>studies, it shows stable bonding pattern with all four targets in compare to other phytochemicals</p><p>and control, shows least score in docking and forms maximum number of hydrogen bonds with</p><p>the active residues of the receptors.</p><p>Conclusion: Based on present observation of docking results, ADME parameters and drug like</p><p>nature, we suggest that morin may be a potent new drug candidate against Covid-19.</p><p>Keywords: COVID-19, coronavirus, drug target, phytochemicals, Drug likeness, ADME,</p><p>docking, morin</p>

scholarly journals Potential Drug Target Identification of Legionella pneumophila by Subtractive Genome Analysis: An In Silico Approach

2019 ◽  
Vol 35 (2) ◽  
pp. 102-107
Author(s):  
Md Sadikur Rahman Shuvo ◽  
Shahriar Kabir Shakil ◽  
Firoz Ahmed
Keyword(s):  
Legionella Pneumophila ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Genomic Analysis ◽  
Opportunistic Pathogen ◽  
Surface Proteins ◽  
Multi Drug Resistance ◽  
Therapeutic Drug ◽  
Homologous Proteins ◽  
Essential Proteins

Though Legionella pneumophila is an opportunistic pathogen, recent reports about multi drug resistance in L. pneumophila is alarming. Annotated whole genome provides a pool of information which is applied for therapeutic drug targets identification in pathogenic bacteria. Subtractive genomic analysis is a pragmatic approach to screen the essential proteins present in pathogen but absent in host. Phylogenetically closely related L. pneumophila str. Philadelphia and L. pneumophila str. ATCC43209 protein profiles were analyzed to identify putative drug targets. Paralogous duplicate profiles were primarily discarded using CD-hit suit. Six hundred and ninety one L. pneumophila str. Philadelphia and 690 L. pneumophila str. ATCC43209 human homologous proteins were excluded using blstP. Among the human non-homologous proteins, the essential proteins for bacteria were separated using DEG tool. For both strains, one hundred and nineteen essential proteins were marked which participate in various metabolic pathways. Among them 11 unique proteins were found. Beside it, 15 and 16 exposed surface proteins were present in strain Philadelphia and ATCC43209 respectively. These unique and cell surface proteins can be utilized for effective drug and vaccine targets. Bangladesh J Microbiol, Volume 35 Number 2 December 2018, pp 102-107

The molecular structure of the μ‎-opioid receptor

2018 ◽  
Author(s):  
Roger D. Knaggs
Keyword(s):  
Crystal Structure ◽  
Side Effects ◽  
Opioid Receptor ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Ligand Interaction ◽  
Analgesic Effects ◽  
Interaction Sites ◽  
Potential Ligand

The landmark paper discussed in this chapter describes the crystal structure of the μ‎-opioid receptor (also known as MOP-1). Opioids are some of the oldest known drugs and have been used for over 4,000 years; however, in addition to having beneficial analgesic effects, they are associated with a myriad of side effects that can minimize their use. Although the gene sequences of the opioid receptors were determined in the 1990s it has taken much longer to translate this into visualizing their three-dimensional structure. The μ‎-opioid receptor consists of seven transmembrane α‎-helices that are connected by three extracellular loops and three intracellular loops, with a wide open binding pocket which offers many potential ligand interaction sites, and evidence of dimerization. Understanding the crystal structure of the μ‎-opioid receptor in much more detail aids explanation of the molecular determinants of ligand recognition and selectivity and will be of use in designing novel opioids with improved efficacy and fewer side effects.

scholarly journals Structure-Guided Approach to Identify Potential Inhibitors of Large Envelope Protein to Prevent Hepatitis B Virus Infection

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Mahboubeh Mehmankhah ◽  
Ruchika Bhat ◽  
Mohammad Sabery Anvar ◽  
Shahnawaz Ali ◽  
Aftab Alam ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
High Throughput Screening ◽  
Three Dimensional ◽  
Surface Protein ◽  
Hbv Infection ◽  
Dimensional Structure ◽  
Amino Acid Residues ◽  
Zinc Database ◽  
B Virus

Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, which can lead to hepatocellular carcinoma. The role of HBV envelope proteins is crucial in viral morphogenesis, infection, and propagation. Thus, blocking the pleiotropic functions of these proteins especially the PreS1 and PreS2 domains of the large surface protein (LHBs) is a promising strategy for designing efficient antivirals against HBV infection. Unfortunately, the structure of the LHBs protein has not been elucidated yet, and it seems that any structure-based drug discovery is critically dependent on this. To find effective inhibitors of LHBs, we have modeled and validated its three-dimensional structure and subsequently performed a virtual high-throughput screening against the ZINC database using RASPD and ParDOCK tools. We have identified four compounds, ZINC11882026, ZINC19741044, ZINC00653293, and ZINC15000762, showing appreciable binding affinity with the LHBs protein. The drug likeness was further validated using ADME screening and toxicity analysis. Interestingly, three of the four compounds showed the formation of hydrogen bonds with amino acid residues lying in the capsid binding region of the PreS1 domain of LHBs, suggesting the possibility of inhibiting the viral assembly and maturation process. The identification of potential lead molecules will help to discover more potent inhibitors with significant antiviral activities.

scholarly journals Relationship Between Drug Targets and Drug-Signature Networks: A Network-Based Genome-Wide Landscape

2021 ◽  
Author(s):  
Chaewon Lee ◽  
Sungmin Kim ◽  
Soonok Sa ◽  
Sang-Min Nam ◽  
Hyun Wook Han
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Drug Effects ◽  
Network Models ◽  
Therapeutic Drug ◽  
Bipartite Network ◽  
Cellular Mechanisms ◽  
Target Network ◽  
Living Organisms ◽  
Approved Drugs

Abstract Drugs produce pharmaceutical and adverse effects that arise from the complex relationship between drug targets and signatures; by considering such relationships, we can begin to understand the cellular mechanisms of drugs. In this study, we selected 463 genes from the DSigDB database corresponding to targets and signatures for 382 FDA-approved drugs with both protein binding information for a drug-target score (KDTN, i.e., the degree to which the protein encoded by the gene binds to a number of drugs) and microarray signature information for a drug-sensitive score (KDSN, i.e., the degree to which gene expression is stimulated by the drug). Accordingly, we constructed two drug–gene bipartite network models, a drug-target network and drug-signature network, which were merged into a multidimensional model. Analysis revealed that the KDTN and KDSN were in mutually exclusive and reciprocal relationships in terms of their biological network structure and gene function. A symmetric balance between the KDTN and KDSN of genes facilitates the possibility of therapeutic drug effects in living organisms. These results provide new insights into the relationship between drugs and genes, specifically drug targets and drug signatures.

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