Ebola virus envelope glycoprotein derived peptide in human Furin-bound state: computational studies

Omotuyi, Idowu Olaposi

doi:10.1080/07391102.2014.981207

Cited by 18 publications

(19 citation statements)

References 31 publications

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“…These two challenges are imposed by the geometric nature of the active site pocket (putative compounds must exhibit electrostatic and geometric fit into the active site and subsites) (Cai et al, 2004;Dahms et al, 2014;I. O. Omotuyi, 2015) and catalytic mechanism (serine protease) of furin (Dahms et al, 2014;I. O. Omotuyi, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Despite a very aggressive rational drug design efforts (Basak et al, 1999;Cai et al, 2004;Dahms et al, 2014;Podsiadlo et al, 2004;Ye et al, 2001), insignificant success has been achieved in terms of drug-likeness and target selectivity. These two challenges are imposed by the geometric nature of the active site pocket (putative compounds must exhibit electrostatic and geometric fit into the active site and subsites) (Cai et al, 2004;Dahms et al, 2014;I. O. Omotuyi, 2015) and catalytic mechanism (serine protease) of furin (Dahms et al, 2014;I.…”

Section: Resultsmentioning

confidence: 99%

“…Methods for 3D plots free energy landscape plot (MATHEMATICA software), graphical representation of data (GRAPHPAD PRISM), and protein snapshots (PyMol) have been discussed elsewhere (O. I. Omotuyi, 2014;I. O. Omotuyi, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, a number of viruses and bacteria depend on furin for processing key pre-proteins. Influenza virus hemagglutinin (Gagnon et al, 2014), HIV-1 glycoprotein gp160 (Moulard, Hallenberger, Garten, & Klenk, 1999), human cytomegalovirus glycoprotein B (Vey et al, 1995), Borna disease virus glycoprotein gp94 (Richt et al, 1998), respiratory syncytial virus fusion protein (Rawling, Cano, Garcin, Kolakofsky, & Melero, 2011), papillomavirus minor capsid protein and L2 proteins (Richards, Lowy, Schiller, & Day, 2006), SARS coronavirus spike glycoprotein (Follis, York, & Nunberg, 2006), H5N1 influenza variant Fujian-like hemagglutinin (Pasquato & Seidah, 2008), varicella-zoster virus glycoprotein B (Oliver et al, 2009), Moloney murine leukemia virus Env precursor (Sjoberg et al, 2014), Middle East respiratory syndrome coronavirus spike protein (Millet & Whittaker, 2014) and Ebola virus envelope glycoprotein (Volchkov, Feldmann, Volchkova, & Klenk, 1998;I. O. Omotuyi, 2015) are processed by furin.…”

Section: Introductionmentioning

confidence: 98%

“…Precursors of transforming growth factor beta 1 (Kahle, Joffroy, Popp, Knabbe, & Stope, 2010), parathyroid hormone (Hendy et al, 1995), beta-secretase (Bennett et al, 2000), membrane type-1 matrix metalloproteinase (Sluijter et al, 2005), von Willebrand factor (Sucic, Moehring, Inocencio, Luchini, & Moehring, 1999), albumin, and beta subunit of nerve growth factor have paired basic amino acid sequence (Arg-X-(Arg/Lys)-Arg′) recognized and cleaved by furin (Dahms et al, 2014;Henrich et al, 2003;I. O. Omotuyi, 2015;Thomas, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Human furin Cys198 imposes dihedral and positional restraints on His194 for optimal Ser386-proton transfer

Omotuyi

Hamada

2015

Journal of Biomolecular Structure and Dynamics

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Inhibitors of human furin may represent the clinical remedy for very aggressive cancer, viral, and bacterial infections. Most of the currently available inhibitors are weak in terms of potency, drug-likeness, and furin specificity thereby necessitating the development of newer compounds especially mechanism-based inhibitors. Here, the roles of active site Cys198 (C198), His194 (H194), and Ser386 (S386) were investigated using computational-site-directed mutagenesis and molecular dynamics (MD) simulation. Data were obtained from six (6) biosystems: wildtype (C198/S386), furin-C198G (S386), furin-S386G (C198), and their peptide (nascent hydrolyzed peptide H2N-RTRR-CO2) bound complexes. The results strongly supported that in wildtype furin but not S386G and C198G mutants, following S386/scissile carbon attack (4.0 Å), the peptide retracted from the active site, representing peptide release post hydrolysis. Furthermore, in S386G mutant, C194 side chain thiolate ion may act as the nucleophile replacement but competing electron-rich centers (H194, H364) and energetically unattainable geometric strain on the peptide may constitute the limiting factors. In biosystems not complexed with peptide (representative of pre-attack state), C198 preferentially engaged H194 imidazole moiety via sulfur-π bond system causing a dihedral and positional restraints on the imidazole ring for ultimate alignment of its NE2 hydrogen atom with the side chain enolate oxygen of S364 required for optimal proton transfer. In summary, small-molecular-weight compounds with dual serine and cysteine protease inhibitory actions may represent a new class of potent and furin-selective compounds for future clinical applications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Human furin Cys198 imposes dihedral and positional restraints on His194 for optimal Ser386-proton transfer

Omotuyi

Hamada

2015

Journal of Biomolecular Structure and Dynamics

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Aframomum melegueta secondary metabolites exhibit polypharmacology against SARS‐CoV‐2 drug targets: in vitro validation of furin inhibition

Omotuyi

Nash

Ajiboye

et al. 2020

Phytotherapy Research

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COVID‐19 pandemic is currently decimating the world's most advanced technologies and largest economies and making its way to the continent of Africa. Weak medical infrastructure and over‐reliance on medical aids may eventually predict worse outcomes in Africa. To reverse this trend, Africa must re‐evaluate the only area with strategic advantage; phytotherapy. One of the many plants with previous antiviral potency is against RNA viruses is Aframomum melegueta. In this study, one hundred (100) A. melegueta secondary metabolites have been mined and computational evaluated for inhibition of host furin, and SARS‐COV‐2 targets including 3C‐like proteinase (Mpro/3CLpro), 2′‐O‐ribose methyltransferase (nsp16) and surface glycoprotein/ACE2 receptor interface. Silica‐gel column partitioning of A. melegueta fruit/seed resulted in 6 fractions tested against furin activity. Diarylheptanoid (Letestuianin A), phenylpropanoid (4‐Cinnamoyl‐3‐hydroxy‐spiro[furan‐5,2′‐(1′H)‐indene]‐1′,2,3′(2′H,5H)‐trione), flavonoids (Quercetin, Apigenin and Tectochrysin) have been identified as high‐binding compounds to SARS‐COV‐2 targets in a polypharmacology manner. Di‐ethyl‐ether (IC50 = 0.03 mg/L), acetone (IC50 = 1.564 mg/L), ethyl‐acetate (IC50 = 0.382 mg/L) and methanol (IC50 = 0.438 mg/L) fractions demonstrated the best inhibition in kinetic assay while DEF, ASF and MEF completely inhibited furin‐recognition sequence containing Ebola virus‐pre‐glycoprotein. In conclusion, A. melegueta and its secondary metabolites have potential for addressing the therapeutic needs of African population during the COVID‐19 pandemic.

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Herbal Lead as Ideal Bioactive Compounds Against Probable Drug Targets of Ebola Virus in Comparison with Known Chemical Analogue: A Computational Drug Discovery Perspective

Setlur

Naik

Skariyachan

2016

Interdiscip Sci Comput Life Sci

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Ebola is a deadly virus that has recently emerged as an enormous public health concern which causes dangerous illness with high fatality rates of 90 %. The virus is not receptive to known antivirals, and hence, there is a promising need to identify novel inhibitors to combat the disease. The present study deals with identification of potential herbal leads that probably subdue the activity of four major drug targets of Ebola virus such as VP24, VP30, VP35 and VP40 by computer-aided virtual screening. The selection of receptors was performed based on their functional roles in the disease. The drug likeliness and ADMET parameters of 150 herbal ligands were computationally predicted. Those molecules that qualified these parameters were preferred for docking studies with the protein targets. An existing chemical antiviral drug, BCX4430 was also docked and its theoretical binding energy was scrutinized. The docking studies suggested that herbal ligand Limonin demonstrated high binding properties with VP24 and VP35 (binding energy -9.7 kcal/mol). Similarly, curcumin exhibited good binding with VP30 (binding energy -9.6 kcal/mol). Further, Mahanine displayed superior interaction with VP40 (binding energy -7.7 kcal/mol). These herbal leads demonstrated better binding potential than the known chemical analogue in the computational studies. This study serves to bestow paramount information for further experimental studies concerning the utility of herbal ligands as probable lead molecules against Ebola viral targets.

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Ebola virus envelope glycoprotein derived peptide in human Furin-bound state: computational studies

Cited by 18 publications

References 31 publications

Human furin Cys198 imposes dihedral and positional restraints on His194 for optimal Ser386-proton transfer

Human furin Cys198 imposes dihedral and positional restraints on His194 for optimal Ser386-proton transfer

Aframomum melegueta secondary metabolites exhibit polypharmacology against SARS‐CoV‐2 drug targets: in vitro validation of furin inhibition

Herbal Lead as Ideal Bioactive Compounds Against Probable Drug Targets of Ebola Virus in Comparison with Known Chemical Analogue: A Computational Drug Discovery Perspective

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