Design, structure-based focusing and in silico screening of combinatorial library of peptidomimetic inhibitors of Dengue virus NS2B-NS3 protease

2010 ◽  
Vol 24 (3) ◽  
pp. 195-212 ◽  
Author(s):  
Vladimir Frecer ◽  
Stanislav Miertus
Keyword(s):  
Dengue Virus ◽  
In Silico ◽  
Combinatorial Library ◽  
In Silico Screening ◽  
Design Structure ◽  
Peptidomimetic Inhibitors ◽  
Ns3 Protease

scholarly journals Structure-Based Design and in Silico Screening of Virtual Combinatorial Library of Benzamides Inhibiting 2-trans Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Predicted Pharmacokinetic Profiles

2019 ◽  
Vol 20 (19) ◽  
pp. 4730
Author(s):  
Koffi Charles Kouman ◽  
Melalie Keita ◽  
Raymond Kre N’Guessan ◽  
Luc Calvin Owono Owono ◽  
Eugene Megnassan ◽  
...  
Keyword(s):  
Gas Phase ◽  
In Silico ◽  
Combinatorial Library ◽  
Acyl Carrier Protein ◽  
Pharmacophore Model ◽  
Qsar Model ◽  
Active Conformation ◽  
In Silico Screening ◽  
Lipinski’S Rule ◽  
Pharmacokinetic Profiles

Background: During the previous decade a new class of benzamide-based inhibitors of 2-trans enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis (Mt) with unusual binding mode have emerged. Here we report in silico design and evaluation of novel benzamide InhA-Mt inhibitors with favorable predicted pharmacokinetic profiles. Methods: By using in situ modifications of the crystal structure of N-benzyl-4-((heteroaryl)methyl) benzamide (BHMB)-InhA complex (PDB entry 4QXM), 3D models of InhA-BHMBx complexes were prepared for a training set of 19 BHMBs with experimentally determined inhibitory potencies (half-maximal inhibitory concentrations IC50exp). In the search for active conformation of the BHMB1-19, linear QSAR model was prepared, which correlated computed gas phase enthalpies of formation (∆∆HMM) of InhA-BHMBx complexes with the IC50exp. Further, taking into account the solvent effect and entropy changes upon ligand, binding resulted in a superior QSAR model correlating computed complexation Gibbs free energies (∆∆Gcom). The successive pharmacophore model (PH4) generated from the active conformations of BHMBs served as a virtual screening tool of novel analogs included in a virtual combinatorial library (VCL) of compounds containing benzamide scaffolds. The VCL filtered by Lipinski’s rule-of-five was screened by the PH4 model to identify new BHMB analogs. Results: Gas phase QSAR model: −log10(IC50exp) = pIC50exp = −0.2465 × ∆∆HMM + 7.95503, R2 = 0.94; superior aqueous phase QSAR model: pIC50exp = −0.2370 × ∆∆Gcom + 7.8783, R2 = 0.97 and PH4 pharmacophore model: p IC 50 exp = 1.0013 × p IC 50 exp − 0.0085, R2 = 0.95. The VCL of more than 114 thousand BHMBs was filtered down to 73,565 analogs Lipinski’s rule. The five-point PH4 screening retained 90 new and potent BHMBs with predicted inhibitory potencies IC50pre up to 65 times lower than that of BHMB1 (IC50exp = 20 nM). Predicted pharmacokinetic profile of the new analogs showed enhanced cell membrane permeability and high human oral absorption compared to current anti-tuberculotics. Conclusions: Combined use of QSAR models that considered binding of the BHMBs to InhA, pharmacophore model, and ADME properties helped to recognize bound active conformation of the benzamide inhibitors, permitted in silico screening of VCL of compounds sharing benzamide scaffold and identification of new analogs with predicted high inhibitory potencies and favorable pharmacokinetic profiles.

scholarly journals Studi in Silico Lima Senyawa Aktif Sebagai Penghambat Protein Virus Dengue

2019 ◽  
pp. 40-47
Author(s):  
Reni Herman
Keyword(s):  
Dengue Virus ◽  
In Silico ◽  
Dengue Infection ◽  
Epigallocatechin Gallate ◽  
Denv Infection ◽  
Virus Protein ◽  
Structural Protein ◽  
The Stability ◽  
The Tropics ◽  
Ns3 Protease

Dengue infection is an endemic disease in the tropics and subtropics, caused by dengue virus (DENV) infection. Some compounds have been shown to have antiviral effects on some viruses. In silico study is conducted to predict the stability of natural ingredient compounds: artemisinin, catechin, mangiferin, epigallocatechin gallate (EGCG), and quercetin in their interactions with dengue virus proteins at molecular level. This study is carried out using the 2008 version of the Molecular Operating Environment (MOE) software. Ligands are ribavirin as antiviral control whereas artemisinin, mangiferin, EGCG, and quercetin with 3D mole format structures. The downloaded DENV protein with PDB document format is the DENV serotype 2 envelope protein with 1OKE code, non structural protein 3 (NS3) with 2VBC code and NS5 protein with 1L9K code. In silico test generally showed that catechin, mangiferin, EGCG, and quercetin had more stable docking ligands to DENV’s proteins. In particular, mangiferin had stable docking ligand to envelope proteins, NS3 (helicase and protease) and in NS5-methyltransferase compared to ribavirin. Catechin stabled on NS3-protease, EGCG on NS3 (helicase and protease) and quercetin on NS3-protease. Artemisinin had less stabled bonds than ribavirin. The results indicated that catechin, mangiferin, EGCG, and quercetin had potential inhibition to DENV proteins whereas mangiferin was the most potential compound to inhibit dengue virus protein targets.

Dengue Virus Inhibition Targets: A Review and Docking Study

2018 ◽  
Vol 18 (18) ◽  
pp. 1522-1530 ◽  
Author(s):  
Luciana Scotti ◽  
Marcus Tullius Scotti ◽  
Nagendra Sastry Yarla ◽  
Alex France Messias Monteiro ◽  
Jessika de Oliveira Viana ◽  
...  
Keyword(s):  
Dengue Virus ◽  
In Silico ◽  
Hemorrhagic Fever ◽  
Docking Study ◽  
World Population ◽  
Protease Inhibition ◽  
Virus Inhibition ◽  
Severe Manifestation ◽  
Density Analysis ◽  
Ns3 Protease

Dengue like any neglected tropical disease affects a large part of the world population. In this disease, the infection is caused by arboviruses transmitted by the A. aegypti and A. albopictus mosquito, in which its most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic of such as fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In the studies shown, in silico tests were performed as molecular docking, functional density analysis, molecular orbitals energies with the analyses of the interactions between bioactives and the targets studied. However, in addition to discussing the fight against dengue virus infection through different routes, in this paper, some in silico results of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism.

scholarly journals The In-silico Studies of Benzylidene Indanone Derivatives Towards Dengue Virus Type-2 NS2B/NS3 Protease

2019 ◽  
Vol 30 (Supp.2) ◽  
pp. 191-198
Author(s):  
Nadirah Zawani Mohd Nesfu ◽  
◽  
Dominique Laurain-Mattar ◽  
Ezatul E. Kamarulzaman ◽  
Habibah A. Wahab ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Virus Type ◽  
In Silico ◽  
In Silico Studies ◽  
Ns3 Protease ◽  
Dengue Virus Type 2

In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses

2009 ◽  
Vol 84 (3) ◽  
pp. 234-241 ◽  
Author(s):  
Thorsten Kampmann ◽  
Ragothaman Yennamalli ◽  
Phillipa Campbell ◽  
Martin J. Stoermer ◽  
David P. Fairlie ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Dengue Virus ◽  
Small Molecule ◽  
In Silico ◽  
Virus Envelope ◽  
In Silico Screening ◽  
E Protein ◽  
Small Molecule Libraries

Gold-Aptamer-Nanoconstructs Engineered to Detect Conserved Enteroviral Nucleic Acid Sequences

2019 ◽  
Author(s):  
Veeren Chauhan ◽  
Mohamed M Elsutohy ◽  
C Patrick McClure ◽  
Will Irving ◽  
Neil Roddis ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
In Silico ◽  
Point Of Care ◽  
Lateral Flow ◽  
Nucleic Acid Sequence ◽  
In Silico Screening ◽  
Lateral Flow Assays ◽  
Life Threatening ◽  
Software And Hardware ◽  
Nucleic Acid Sequences

<p>Enteroviruses are a ubiquitous mammalian pathogen that can produce mild to life-threatening disease. Bearing this in mind, we have developed a rapid, accurate and economical point-of-care biosensor that can detect a nucleic acid sequences conserved amongst 96% of all known enteroviruses. The biosensor harnesses the physicochemical properties of gold nanoparticles and aptamers to provide colourimetric, spectroscopic and lateral flow-based identification of an exclusive enteroviral RNA sequence (23 bases), which was identified through in silico screening. Aptamers were designed to demonstrate specific complementarity towards the target enteroviral RNA to produce aggregated gold-aptamer nanoconstructs. Conserved target enteroviral nucleic acid sequence (≥ 1x10<sup>-7</sup> M, ≥1.4×10<sup>-14</sup> g/mL), initiates gold-aptamer-nanoconstructs disaggregation and a signal transduction mechanism, producing a colourimetric and spectroscopic blueshift (544 nm (purple) > 524 nm (red)). Furthermore, lateral-flow-assays that utilise gold-aptamer-nanoconstructs were unaffected by contaminating human genomic DNA, demonstrated rapid detection of conserved target enteroviral nucleic acid sequence (< 60 s) and could be interpreted with a bespoke software and hardware electronic interface. We anticipate our methodology will translate in-silico screening of nucleic acid databases to a tangible enteroviral desktop detector, which could be readily translated to related organisms. This will pave-the-way forward in the clinical evaluation of disease and complement existing strategies at overcoming antimicrobial resistance.</p>

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