scholarly journals Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257916
Author(s):  
Farzin Sohraby ◽  
Hassan Aryapour
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Stacking Interactions ◽  
Aromatic Residues ◽  
Efficacious Treatment ◽  
The Stability ◽  
Flap Region ◽  
Hiv 1

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and to discover the reasons for the lack of inhibitory activity of Indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of Indinavir reached over 40 Å. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98′ and Phe67/Phe67′ in the HTLV-1 protease could make strong π-Stacking interactions with Indinavir in the unbinding pathway, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and selective inhibitors for the HTLV-1 protease.

scholarly journals Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by Supervised Molecular Dynamics simulation

2021 ◽  
Author(s):  
Farzin Sohraby ◽  
Hassan Aryapour
Keyword(s):  
Inhibitory Activity ◽  
Antiviral Drug ◽  
Good Explanation ◽  
Dynamics Simulation ◽  
Stacking Interactions ◽  
Pi Stacking ◽  
Efficacious Treatment ◽  
The Stability ◽  
Flap Region ◽  
Hiv 1

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing SuMD method, we reconstructed the unbinding pathways of indinavir from HIV and HTLV-1 proteases in order to compare and to understand the mechanism of the unbinding, and also to discover the reasons for the lack of inhibitory activity of indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of indinavir reached over 4 nm. Also, we found that the mobility and the fluctuations of the flap region is higher in the HTLV-1 protease which makes the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease can make strong pi-Stacking interactions with indinavir in the unbinding pathway which are unfavorable for the stability of indinavir in the active site. The details found in this study can make a good explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can be a great assist for designing more effective and more selective inhibitors for the HTLV-1 protease.

scholarly journals Penambatan Molekuler dan Simulasi Dinamika Molekuler Senyawa Dari Genus Nigella Terhadap Penghambatan Aktivitas Enzim Protease HIV-1

2020 ◽  
Vol 6 (1) ◽  
pp. 132-140
Author(s):  
Muhammad Sulaiman Zubair ◽  
Saipul Maulana ◽  
Alwiyah Mukaddas
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Amino Acid ◽  
Active Site ◽  
Inhibitory Activity ◽  
Nigella Sativa ◽  
Dynamics Simulation ◽  
Protease Enzyme ◽  
Enzyme Model ◽  
Hiv 1

Nigella plant genus has potential as anti-HIV. One species of Nigella, Nigella sativa has been reported to have HIV-1 protease enzyme inhibitory activity. This research aims to determine the compounds of the Nigella genus that have activity as HIV-1 protease enzyme inhibitory activity through molecular docking method by Autodock Vina and to compare interaction stability through molecular dynamics simulations by AMBER. The metabolite of the Nigella genus was obtained from the KnapSack website, and enzyme model was obtained from the Protein Data Bank (3NU3). The results of molecular docking found the lowest affinity energy of Nigella compound is Nigellidine 4-O-sulfite (-13.4 kcal/mol). Meanwhile, the affinity energy of the ligand native (Amprenavir) was -12.1 kcal/mol. The lowest affinity energy of Nigellidine 4-O-sulfite might be predicted to have potency as an HIV-1 Protease inhibitor. Molecular dynamics simulation showed Root Mean Square Fluctuation (RMSF) value of Nigellidine 4-O-sulfite with the amino acid active site is 0.4064 Å for ASP:25 and 0.5667 Å for ASP: 125. Whereas RMSF ligand native with the amino acid active site, ASP: 25 is 0.3647 Å and ASP: 125 is 0.3639 Å. The higher RMSF value of Nigellidine 4-O-sulfite describes the lower interaction stability than the ligand native.

Xanthine oxidase inhibitory activity of Euphorbia peplus L. phenolics

2021 ◽  
Vol 24 ◽  
Author(s):  
Emadeldin M. Kamel ◽  
Noha A. Ahmed ◽  
Ashraf A. El-Bassuony ◽  
Omnia E. Hussein ◽  
Barakat Alrashdi ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Radius Of Gyration ◽  
Euphorbia Peplus

Background: Various phenolics show inhibitory activity towards xanthine oxidase (XO), an enzyme that generates reactive oxygen species which cause oxidative damage. Objective: This study investigated the XO inhibitory activity of Euphorbia peplus phenolics. Methods: The dried powdered aerial parts of E. peplus were extracted, fractioned and phenolics were isolated and identified. The XO inhibitory activity of E. peplus extract (EPE) and the isolated phenolics was investigated in vitro and in vivo. Results: Three phenolics were isolated from the ethyl acetate fraction of E. peplus. All isolated compounds and the EPE showed inhibitory activity towards XO in vitro. In hyperuricemic rats, EPE and the isolated phenolics decreased uric acid and XO activity. Molecular docking showed the binding modes of isolated phenolics with XO, depicting significant interactions with the active site amino acid residues. Molecular dynamics simulation trajectories confirmed the interaction of isolated phenolics with XO by forming hydrogen bonds with the active site residues. Also, the root mean square (RMS) deviations of XO and phenolics-XO complexes achieved equilibrium and fluctuated during the 10 ns MD simulations. The radius of gyration and solvent accessible surface area investigations showed that different systems were stabilized at ≈ 2500 ps. The RMS fluctuations profile depicted that the drug binding site exhibited a rigidity behavior during the simulation. Conclusion: In vitro, in vivo and computational investigations showed the XO inhibitory activity of E. peplus phenolics. These phenolics might represent promising candidates for the development of XO inhibitors.

scholarly journals Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Hironori Hayashi ◽  
Haydar Bulut ◽  
Kalapala Venkateswara Rao ◽  
Prasanth R. Nyalapatla ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Active Site ◽  
Fluorine Atom ◽  
Halogen Bond ◽  
The Novel ◽  
Wild Type ◽  
Flap Region ◽  
Hiv 1

ABSTRACTWe generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 havemeta-monofluorophenyl andpara-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 μM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1DRVRP30), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC50of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PRWT) complexed with the novel PIs revealed that GRL-001-15’smeta-fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81′ (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81′, Ile82′, and Arg8′. In contrast, GRL-003-15 forms halogen bond interactions with Pro81′ alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

Homology Modeling and Evaluation of Sars-Cov-2 Spike Protein Mutant

2021 ◽  
Vol 6 (4) ◽  
pp. 38-55
Author(s):  
Hima Vyshnavi ◽  
Aswin Mohan ◽  
Shahanas Naisam ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Structure Modeling ◽  
Ramachandran Plot ◽  
Global Pandemic ◽  
The Stability

Severe acute respiratory syndrome coronavirus 2 (SARS‐Cov-2), a global pandemic, affected the world, increasing every day. A mutated variant D614G, showing more virulence and transmission, was studied for forecasting the emergence of more virulent and pathogenic viral strains. This study focuses on structure modeling and validation. Characterization of proteins homologous to wild spike protein was done, and homology models of the mutated variant were modeled using these proteins. Validation of models was done using Ramachandran plot and ERRAT plot. Molecular dynamics simulation was used to validate the stability of the models, and binding affinity of these models were estimated by molecular docking with an approved antiviral drug. Docked complexes were studied and the best model was selected. Molecular dynamics simulation was used to estimate the stability of the docked complex. The model of 6VXX, a homologous of wild spike protein, was found to be stable with the interaction of the antiviral drug from this study.

Three Major Phosphoacceptor Sites in HIV-1 Capsid Protein Enhances its Structural Stability and Resistance Against the Inhibitor: Explication Through Molecular Dynamics Simulation, Molecular Docking and DFT Analysis

2020 ◽  
Vol 23 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Nouman Rasool ◽  
Waqar Hussain
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Capsid Protein ◽  
Structural Stability ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Maximum Stability ◽  
The Stability ◽  
Hiv 1

Background: Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus, which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it. Objective: The aim of this study was to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it’s binding with GS-CA1, a novel potent inhibitor. Method: Eight complexes were analyzed and Molecular Dynamics (MD) simulations were performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis. Results: The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5 kcal/mol (Ki = 0.579 µM). Conclusion: These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

scholarly journals Plasticity of the 340-Loop in Influenza Neuraminidase Offers New Insight for Antiviral Drug Development

2020 ◽  
Vol 21 (16) ◽  
pp. 5655
Author(s):  
Nanyu Han ◽  
Justin Tze Yang Ng ◽  
Yanpeng Li ◽  
Yuguang Mu ◽  
Zunxi Huang
Keyword(s):  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Side Chain ◽  
Structure Based Drug Design ◽  
Sialic Acid Binding ◽  
The Stability ◽  
First Time ◽  
Side Chain Orientation ◽  
Simulation Time

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342–347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 μs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.

Role of the N-terminus in human 4-hydroxyphenylpyruvate dioxygenase activity

2019 ◽  
Vol 167 (3) ◽  
pp. 315-322
Author(s):  
An-Ning Feng ◽  
Chih-Wei Huang ◽  
Chi-Huei Lin ◽  
Yung-Lung Chang ◽  
Meng-Yuan Ni ◽  
...  
Keyword(s):  
Active Site ◽  
Catalytic Efficiency ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Catalytic Function ◽  
C Terminus ◽  
N Terminus ◽  
Key Enzyme ◽  
The Stability

Abstract 4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a key enzyme in tyrosine catabolism, catalysing the oxidation of 4-hydroxyphenylpyruvate to homogentisate. Genetic deficiency of this enzyme causes type III tyrosinaemia. The enzyme comprises two barrel-shaped domains formed by the N- and C-termini, with the active site located in the C-terminus. This study investigated the role of the N-terminus, located at the domain interface, in HPPD activity. We observed that the kcat/Km decreased ∼8-fold compared with wild type upon removal of the 12 N-terminal residues (ΔR13). Interestingly, the wild-type level of activity was retained in a mutant missing the 17 N-terminal residues, with a kcat/Km 11-fold higher than that of the ΔR13 mutant; however, the structural stability of this mutant was lower than that of wild type. A 2-fold decrease in catalytic efficiency was observed for the K10A and E12A mutants, indicating synergism between these residues in the enzyme catalytic function. A molecular dynamics simulation showed large RMS fluctuations in ΔR13 suggesting that conformational flexibility at the domain interface leads to lower activity in this mutant. These results demonstrate that the N-terminus maintains the stability of the domain interface to allow for catalysis at the active site of HPPD.

scholarly journals Structural Adaptation of Darunavir Analogs Against Primary Resistance Mutations in HIV-1 Protease

2018 ◽  
Author(s):  
Gordon J. Lockbaum ◽  
Florian Leidner ◽  
Linah N. Rusere ◽  
Mina Henes ◽  
Klajdi Kosovrasti ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Crystal Structures ◽  
Active Site ◽  
Active Site Residues ◽  
Resistance Mutations ◽  
Structural Adaptation ◽  
Primary Resistance ◽  
Principle Component ◽  
Flap Region ◽  
Hiv 1

AbstractHIV-1 protease is one of the prime targets of agents used in antiretroviral therapy against HIV. However, under selective pressure of protease inhibitors, primary mutations at the active site weaken inhibitor binding to confer resistance. Darunavir (DRV) is the most potent HIV-1 protease inhibitor in clinic; resistance is limited, as DRV fits well within the substrate envelope. Nevertheless, resistance is observed due to hydrophobic changes at residues including I50, V82 and I84 that line the S1/S1’ pocket within the active site. Through enzyme inhibition assays and a series of 12 crystal structures, we interrogated susceptibility of DRV and two potent analogs to primary S1’ mutations. The analogs had modifications at the hydrophobic P1’ moiety to better occupy the unexploited space in the S1’ pocket where the primary mutations were located. Considerable losses of potency were observed against protease variants with I84V and I50V mutations for all three inhibitors. The crystal structures revealed an unexpected conformational change in the flap region of I50V protease bound to the analog with the largest P1’ moiety, indicating interdependency between the S1’ subsite and the flap region. Collective analysis of protease-inhibitor van der Waals (vdW) interactions in the crystal structures using principle component analysis indicated I84V mutation underlying the largest variation in the vdW contacts. Interestingly, the principle components were able to distinguish inhibitor identity and relative potency solely based on vdW interactions of active site residues in the crystal structures. Our results reveal the interplay between inhibitor P1’ moiety and primary S1’ mutations, as well as suggesting a novel method for distinguishing the interdependence of resistance through principle component analyses.

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