scholarly journals In silico screening of natural products targeting chorismate synthase

2019 ◽  
Vol 7 (1) ◽  
pp. 1-9
Author(s):  
Mohammed Zaghlool Al-Khayyat
Keyword(s):  
Antibacterial Agents ◽  
Binding Affinities ◽  
In Silico Screening ◽  
Chorismate Synthase ◽  
Glycoprotein I ◽  
P Glycoprotein ◽  
Enzyme Model ◽  
Oxidation Stage ◽  
Predicted Model ◽  
Acid Pathway

Introduction: Chorismate synthase catalyzes the final step in shikimate  acid pathway involved in synthesis of aromatic compounds in bacteria.This enzyme can be a possible molecular target for design of antibiotics. Materials and Methods: Homology modeling and molecular dockingwere performed to screen about one hundred natural compounds in order to find inhibitors of enzymes as a possible new target. A model wasbuilt by SWISS-MODEL and its quality was assessed by ERRAT, ProSA, Rampage and MolProbity servers. Docking experiments were performedand pharmacokinetics and toxicities were studied by admetSAR. Results: The predicted model was reliable to be used in docking experiments.Amentoflavone had the highest binding affinity of -10.0 Kcal/mol. Probabilities indicated that rotenone may inhibit P-glycoprotein I, hinokiflavone and silybin may inhibit P-glycoprotein II, while taspine acts on both types of P-glycoproteins. Amentofalavone, hinokiflavone, rotenone and silybin have a probability of inhibiting cytochromes that are involved in oxidation stage of metabolism. Conclusions: These compounds had binding affinities towards FMN binding site of the enzyme model and may be considered in the research for new antibacterial agents but only when their drug interactions are fully investigated.

scholarly journals In silico screening for natural ligands to non-structural nsp7 conformers of SARS coronaviruses

2020 ◽  
Author(s):  
Rafael Blasco ◽  
Julio Coll
Keyword(s):  
Chemical Properties ◽  
Clinical Work ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Structural Protein ◽  
In Silico Screening ◽  
Natural Ligands ◽  
Final Optimization ◽  
Scoring Algorithms

<p>The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are uniquely conserved small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Drugs with potential to interfere with nsp7s have not been described yet. Despite the difficulties of having no previously defined binding pocket, high-throughput blind screening of more than one hundred thousand natural compounds < 400 Dalton of molecular weight docked against the nsp7.1ysy conformer identified hundreds of leads displaying predicted high binding-affinities by AutoDockVina. The leads were then docked to 14 nsp7 available conformers by two different binding scoring algorithms ( AutoDockVina-PyRx and HYDE-seeSAR), to identify consensus top-leads. Further predictive analysis of their physiological/toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands, most of them showing steroid-like structures closely related to some of those being actually used in clinical work. A final optimization by search for structural similarities to the drug-like top-lead, yielded a collection of novel steroid-like ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated since they are available. Additionally, these nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses<br></p>

scholarly journals In Silico Screening for Inhibitors of P-Glycoprotein That Target the Nucleotide Binding Domains

2014 ◽  
Vol 86 (6) ◽  
pp. 716-726 ◽  
Author(s):  
Frances K. Brewer ◽  
Courtney A. Follit ◽  
Pia D. Vogel ◽  
John G. Wise
Keyword(s):  
In Silico ◽  
Nucleotide Binding ◽  
In Silico Screening ◽  
Binding Domains ◽  
P Glycoprotein

scholarly journals In silico screening for natural ligands to non-structural nsp7 conformers of SARS coronaviruses

2020 ◽  
Author(s):  
Rafael Blasco ◽  
Julio Coll
Keyword(s):  
Chemical Properties ◽  
Clinical Work ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Structural Protein ◽  
In Silico Screening ◽  
Natural Ligands ◽  
Final Optimization ◽  
Scoring Algorithms

<p>The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are uniquely conserved small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Drugs with potential to interfere with nsp7s have not been described yet. Despite the difficulties of having no previously defined binding pocket, high-throughput blind screening of more than one hundred thousand natural compounds < 400 Dalton of molecular weight docked against the nsp7.1ysy conformer identified hundreds of leads displaying predicted high binding-affinities by AutoDockVina. The leads were then docked to 14 nsp7 available conformers by two different binding scoring algorithms ( AutoDockVina-PyRx and HYDE-seeSAR), to identify consensus top-leads. Further predictive analysis of their physiological/toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands, most of them showing steroid-like structures closely related to some of those being actually used in clinical work. A final optimization by search for structural similarities to the drug-like top-lead, yielded a collection of novel steroid-like ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated since they are available. Additionally, these nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses<br></p>

scholarly journals Computational Pharmacogenetics of P-Glycoprotein Mediated Antiepileptic Drug Resistance

2018 ◽  
Vol 11 (1) ◽  
pp. 197-207 ◽  
Author(s):  
Sindhu Varghese ◽  
Ashok Palaniappan
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Conformational Changes ◽  
Binding Sites ◽  
Docking Studies ◽  
Drug Binding ◽  
Experimental Investigations ◽  
Binding Affinities ◽  
Drug Binding Site ◽  
P Glycoprotein

Background:The treatment of epilepsy using antiepileptogenic drugs is complicated by drug resistance, resulting in treatment failure in more than one-third of cases. Human P-glycoprotein (hPGP;MDR1) is a known epileptogenic mediator.Methods:Given that experimental investigations have suggested a role for pharmacogenetics in this treatment failure, it would be of interest to study hPGP polymorphisms that might contribute to the emergence of drug resistance. Changes in protein functional activity could result from mutations as well as altered abundance. Bioinformatics approaches were used to assess and rank the functional impact of 20 missenseMDR1polymorphisms and the top five were selected. The structures of the wildtype and variant hPGP were modelled based on the mouse PGP structure. Docking studies of the wildtype and variant hPGP with four standard anti-epileptic drugs were carried out.Results:Our results revealed that the drug binding site with respect to the wildtype protein was uniform. However, the variant hPGP proteins displayed a repertoire of binding sites with stronger binding affinities towards the drug.Conclusion:Our studies indicated that specific polymorphisms inMDR1could drive conformational changes of PGP structure, facilitating altered contacts with drug-substrates and thus modifying their bioavailability. This suggests thatMDR1polymorphisms could actively contribute to the emergence of pharmaco-resistance in antiepileptic therapy.

scholarly journals Comprehensive In Silico Screening of the Antiviral Potentialities of a New Humulene Glucoside from Asteriscus hierochunticus against SARS-CoV-2

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Vincent O. Imieje ◽  
Ahmed A. Zaki ◽  
Ahmed M. Metwaly ◽  
Ahmad E. Mostafa ◽  
Eslam B. Elkaeed ◽  
...  
Keyword(s):  
In Silico ◽  
Chemical Structure ◽  
Nonstructural Protein ◽  
2D Nmr ◽  
Binding Affinities ◽  
In Silico Screening ◽  
Main Protease ◽  
Whole Plant ◽  
Isolated Compound

Chromatographic fractionation of the methanolic extract of Asteriscus hierochunticus whole plant led to the identification of a new humulene glucoside (1). The chemical structure of the isolated compound was elucidated by IR, 1D, 2D NMR, and HRESIMS data analysis to be (-)-(2Z,6E,9E)8α-hydroxy-2,6,9-humulatrien-1(12)-olide. In this study, we report the in silico binding affinities of 1 against four different SARS-CoV-2 proteins (COVID-19 main protease (PDB ID: 6lu7), nonstructural protein (PDB ID: 6W4H), RNA-dependent RNA polymerase (PDB ID: 7BV2), and SARS-CoV-2 helicase (PDB ID: 5RMM)). The isolated compound showed excellent binding affinity values (ΔG) of −21.65, −20.05, −28.93, and −21.73 kcal/mol, respectively, against the target proteins compared to the cocrystallized ligands that exhibited ΔG values of −23.75, −17.65, −23.57, and −15.30 kcal/mol, respectively. Further in silico investigations of the isolated compound (1) for its ADMET and toxicity profiles revealed excellent drug likeliness. On the other hand, the results obtained from in vitro antitrypanosomal, antileishmanial, and antimalarial activities of (1) were not promising.

Specificity determinants of phosphoprotein phosphatases controlling kinetochore functions

2020 ◽  
Vol 64 (2) ◽  
pp. 325-336 ◽  
Author(s):  
Dimitriya H. Garvanska ◽  
Jakob Nilsson
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Activity Level ◽  
Phosphorylation Sites ◽  
Binding Affinities ◽  
Mitotic Kinases ◽  
Anaphase Onset ◽  
Phosphoprotein Phosphatases ◽  
Linear Motifs ◽  
Temporal And Spatial ◽  
Kinetochore Function

Abstract Kinetochores are instrumental for accurate chromosome segregation by binding to microtubules in order to move chromosomes and by delaying anaphase onset through the spindle assembly checkpoint (SAC). Dynamic phosphorylation of kinetochore components is key to control these activities and is tightly regulated by temporal and spatial recruitment of kinases and phosphoprotein phosphatases (PPPs). Here we focus on PP1, PP2A-B56 and PP2A-B55, three PPPs that are important regulators of mitosis. Despite the fact that these PPPs share a very similar active site, they target unique ser/thr phosphorylation sites to control kinetochore function. Specificity is in part achieved by PPPs binding to short linear motifs (SLiMs) that guide their substrate specificity. SLiMs bind to conserved pockets on PPPs and are degenerate in nature, giving rise to a range of binding affinities. These SLiMs control the assembly of numerous substrate specifying complexes and their position and binding strength allow PPPs to target specific phosphorylation sites. In addition, the activity of PPPs is regulated by mitotic kinases and inhibitors, either directly at the activity level or through affecting PPP–SLiM interactions. Here, we discuss recent progress in understanding the regulation of PPP specificity and activity and how this controls kinetochore biology.

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