A comprehensive in silico study towards understanding the inhibitory mechanism of Lactoperoxidase by Dapsone and Propofol

2020 ◽  
Vol 16 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Gizachew Muluneh Amera ◽  
Jayaraman Muthukumaran ◽  
Rashmi Prabha Singh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Protoporphyrin Ix ◽  
Md Simulations ◽  
Prosthetic Group ◽  
Drug Molecules ◽  
Group A ◽  
Complex Forms ◽  
Covalently Linked

Introduction: Lactoperoxidase (LPO) is a member of mammalian heme peroxidase family and is an enzyme of innate immune system. It possesses a covalently linked heme prosthetic group (a derivative of protoporphyrin IX) in its active site. LPO catalyzes the oxidation of halides and pseudohalides in the presence of hydrogen peroxide (H2O2) and shows a broad range of antimicrobial activity. Methods: In this study, we have used two pharmaceutically important drug molecules, namely dapsone and propofol, which are earlier reported as potent inhibitors of LPO. Whereas the stereochemistry and mode of binding of dapsone and propofol to LPO is still not known because of the lack of the crystal structure of LPO with these two drugs. In order to fill this gap, we utilized molecular docking and molecular dynamics (MD) simulation studies of LPO in native and complex forms with dapsone and propofol. Results: From the docking results, the estimated binding free energy (ΔG) of -9.25 kcal/mol (Ki = 0.16 μM) and -7.05 kcal/mol (Ki = 6.79 μM) was observed for dapsone, and propofol, respectively. The standard error of Auto Dock program is 2.5 kcal/mol; therefore, molecular docking results alone were inconclusive. Conclusion: To further validate the docking results, we performed MD simulation on unbound, and two drugs bounded LPO structures. Interestingly, MD simulations results explained that the structural stability of LPO-Propofol complex was higher than LPO-Dapsone complex. The results obtained from this study establish the mode of binding and interaction pattern of the dapsone and propofol to LPO as inhibitors.

Design of potential IKK-β inhibitors using molecular docking and molecular dynamics techniques for their anti-cancer potential

2020 ◽  
Vol 16 ◽  
Author(s):  
Salam Pradeep Singh ◽  
Iftikar Hussain ◽  
Bolin Kumar Konwar ◽  
Ramesh Chandra Deka ◽  
Chingakham Brajakishor Singh
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Md Simulation ◽  
Inflammatory Diseases ◽  
Binding Free Energy ◽  
Anti Cancer ◽  
Dietary Phytochemicals ◽  
Toxicity Analysis ◽  
The Stability ◽  
Stable Trajectory

Aim and Objective: To evaluate a set of seventy phytochemicals for their potential ability to bind the inhibitor of nuclear factor kappaB kinase beta (IKK-β) which is a prime target for cancer and inflammatory diseases. Materials and Methods: Seventy phytochemicals were screened against IKK-β enzyme using DFT-based molecular docking technique and the top docking hits were carried forward for molecular dynamics (MD) simulation protocols. The adme-toxicity analysis was also carried out for the top docking hits. Results: Sesamin, matairesinol and resveratrol were found to be the top docking hits with a total score of -413 kJ/mol, -398.11 kJ/mol and 266.73 kJ/mol respectively. Glu100 and Gly102 were found to be the most common interacting residues. The result from MD simulation observed a stable trajectory with a binding free energy of -107.62 kJ/mol for matairesinol, -120.37 kJ/mol for sesamin and -40.56 kJ/mol for resveratrol. The DFT calculation revealed the stability of the compounds. The ADME-Toxicity prediction observed that these compounds fall within the permissible area of Boiled-Egg and it does not violate any rule for pharmacological criteria, drug-likeness etc. Conclusion: The study interprets that dietary phytochemicals are potent inhibitors of IKK-β enzyme with favourable binding affinity and less toxic effects. In fact, there is a gradual rise in the use of plant-derived molecules because of its lesser side effects compared to chemotherapy. The study has also provided an insight by which the phytochemicals inhibited the IKK-β enzyme. The investigation would also provide in understanding the inhibitory mode of certain dietary phytochemicals in treating cancer.

scholarly journals Virtual Screening and Free Energy Estimation for Identifying Mycobacterium Tuberculosis Flavoenzyme DprE1 Inhibitors

2020 ◽  
Author(s):  
Niranjan Kumar ◽  
Rakesh Srivastava ◽  
Amresh Prakash ◽  
Andrew M Lynn
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Energy Estimation ◽  
Chemical Libraries ◽  
Drug Molecules ◽  
Rational Drug ◽  
Drug Designing

<p>we investigated the promising MTB drug target protein, DprE1 (decaprenylphosphoryl-β-d-ribose 2’-epimerase), involve in cell was synthesis of Mycobacterium tuberculosis and plays a crucial role<b> </b>in host pathogenesis, virulence, lethality and survival under stress. Considering the emergence of different variants of drug resistant MTB are one of the major threats worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we employed comprehensive computational methods for the structure based virtual screening of bioactive anti-tuberculosis compounds from chemical libraries ChEMBL, characterized the physicochemical properties analyses and the trajectories obtained from MD simulations were used for estimation of binding free energy, applying molecular theory of solvation (MM/PBSA, MM/GBSA AND MM/3DRISM-KH). All results were compared with known DprE1 inhibitors. Our studies suggest that four compounds (ChEMBL2441313, ChEMBL2338605, ChEMBL441373 and ChEMBL1607606) compounds may be explored as lead molecules for the rational drug designing of DprE1-inhibitors in MTB therapy.</p><br>

scholarly journals Mutagenesis of DsbAss is Crucial for the Signal Recognition Particle Mechanism in Escherichia coli: Insights from Molecular Dynamics Simulations

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 133 ◽  
Author(s):  
Faiza Durrani ◽  
Roquyya Gul ◽  
Muhammad Mirza ◽  
Naheed Kaderbhai ◽  
Matheus Froeyen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Molecular Dynamics ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Signal Sequence ◽  
Binding Free Energy ◽  
Signal Recognition Particle ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Dynamics Simulations

The disulfide bond signal sequence (DsbAss) protein is characterized as an important virulence factor in gram-negative bacteria. This study aimed to analyze the “alanine” alteration in the hydrophobic (H) region of DsbAss and to understand the conformational DsbAss alteration(s) inside the fifty-four homolog (Ffh)-binding groove which were revealed to be crucial for translocation of ovine growth hormone (OGH) to the periplasmic space in Escherichia coli via the secretory (Sec) pathway. An experimental design was used to explore the hydrophobicity and alteration of alanine (Ala) to isoleucine (Ile) in the tripartite structure of DsbAss. As a result, two DsbAss mutants (Ala at positions -11 and -13) with same hydrophobicity of 1.539 led to the conflicting translocation of the active OGH gene. We performed molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GBSA) binding free energy calculations to examine the interaction energetic and dynamic aspects of DsbAss/signal repetition particle 54 (SRP54) binding, which has a principle role in Escherichia coli Sec pathways. Although both DsbAss mutants retained helicity, the MD simulation analysis evidenced that altering Ala-13 changed the orientation of the signal peptide in the Ffh M binding domain groove, favored more stable interaction energies (MM-GBSA ΔGtotal = −140.62 kcal mol−1), and hampered the process of OGH translocation, while Ala-11 pointed outward due to unstable conformation and less binding energy (ΔGtotal = −124.24 kcal mol−1). Here we report the dynamic behavior of change of “alanine” in the H-domain of DsbAss which affects the process of translocation of OGH, where MD simulation and MM-GBSA can be useful initial tools to investigate the virulence of bacteria.

scholarly journals (E)-4-(3-(3-(4-Methoxyphenyl)acryloyl)phenoxy)butyl 2-Hydroxybenzoate

Molbank ◽  
10.3390/m1195 ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. M1195
Author(s):  
Ihsan Ikhtiarudin ◽  
Rahma Dona ◽  
Neni Frimayanti ◽  
Rahayu Utami ◽  
Emma Susanti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Title Compound ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Docking Study ◽  
2D Nmr ◽  
Molecular Docking Study ◽  
Hybrid Compound ◽  
Before And After

A new hybrid compound of chalcone-salicylate (title compound) has been successfully synthesized using a linker mode approach under reflux condition. The structure of the title compound has been established by spectroscopic analysis including UV-Vis, FT-IR, HRMS, 1D, and 2D NMR. Then, computational approach was also applied in this study through molecular docking and MD simulation to explore its potency against breast cancer. The results of the molecular docking study showed that the title compound exhibited more negative value of binding free energy (−8.15 kcal/mol) than tamoxifen (−7.00 kcal/mol). In addition, no striking change in the positioning of the interacting residues was recorded before and after the MD simulations. Based on the studies, it can be predicted that the title compound has a cytotoxic activity potency against breast cancer through ERα inhibition and it presumably can be developed as anticancer agent candidate.

scholarly journals Synthesis of haem cytochrome c prosthetic group from δ-aminolaevulinate by the cell sap from rat liver

1977 ◽  
Vol 166 (3) ◽  
pp. 305-313 ◽  
Author(s):  
Carmen Sáez De Córdova ◽  
Regina Cohén ◽  
Néstor F. González-Cadavid
Keyword(s):  
Cytochrome C ◽  
Rat Liver ◽  
Paper Chromatography ◽  
Protoporphyrin Ix ◽  
Soluble Form ◽  
Prosthetic Group ◽  
Small Pool ◽  
Complete Set ◽  
Covalently Linked

To determine whether the prosthetic group of cytochrome c is synthesized and linked to the apoprotein in the cytosol or in connexion with the endoplasmic reticulum, we have studied the incorporation in vitro of δ-amino[14C]laevulinate into porphyrin compounds and cytochrome c by the cell sap from rat liver. The radioactive precursor was incorporated into a trichloroacetic acid-precipitable form partially resistant to extractions by acid solvents, suggesting the existence of a fraction covalently linked to protein. The activity was proportional to the amount of protein incubated, did not increase substantially by supplementation with the microsomal fraction and an energy source, and was very low in the pH5 fraction. Addition of increasing amounts of haemin inhibited the incorporation, as with purified δ-aminolaevulinate dehydratase. [14C]Protoporphyrin IX was identified by paper chromatography, together with a shoulder running as protohaem IX. The cell sap in the absence of ribosomes was also able to incorporate radioactivity into purified cytochrome c, and the addition of ribosomes significantly enhanced the activity. The precursors of haem c were synthesized in the soluble system by the known haem-synthetic pathway, as shown by the kinetics of labelling of the coproporphyrin, protoporphyrin and haem fractions, and the activities were concentrated in the precipitate obtained between 40 and 60% saturation with (NH4)2SO4. The presence of ferrochelatase was indicated by the incorporation of55Fe into proto- and haemato-haem identified by paper chromatography. It is concluded that the cell sap from rat liver contains the complete set of enzymes for the synthesis from δ-aminolaevulinate of haem c and its linkage to a small pool of free apoprotein c present in soluble form. This suggests that an ancillary pathway of haem synthesis occurs in the cytosol for at least the formation of the prosthetic group, which is linked post-translationally to that pool of apoprotein c synthesized by free polyribosomes.

scholarly journals 3D-QSAR, Molecular Docking, and MD Simulations of Anthraquinone Derivatives as PGAM1 Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuwei Wang ◽  
Yifan Guo ◽  
Shaojia Qiang ◽  
Ruyi Jin ◽  
Zhi Li ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Rational Design ◽  
Binding Free Energy ◽  
3D Qsar ◽  
Md Simulations ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Wide Range ◽  
Anthraquinone Derivatives

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure–activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure–activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.

scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals Virtual Screening and Free Energy Estimation for Identifying Mycobacterium Tuberculosis Flavoenzyme DprE1 Inhibitors

2020 ◽  
Author(s):  
Niranjan Kumar ◽  
Rakesh Srivastava ◽  
Amresh Prakash ◽  
Andrew M Lynn
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Energy Estimation ◽  
Chemical Libraries ◽  
Drug Molecules ◽  
Rational Drug ◽  
Drug Designing

<p>we investigated the promising MTB drug target protein, DprE1 (decaprenylphosphoryl-β-d-ribose 2’-epimerase), involve in cell was synthesis of Mycobacterium tuberculosis and plays a crucial role<b> </b>in host pathogenesis, virulence, lethality and survival under stress. Considering the emergence of different variants of drug resistant MTB are one of the major threats worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we employed comprehensive computational methods for the structure based virtual screening of bioactive anti-tuberculosis compounds from chemical libraries ChEMBL, characterized the physicochemical properties analyses and the trajectories obtained from MD simulations were used for estimation of binding free energy, applying molecular theory of solvation (MM/PBSA, MM/GBSA AND MM/3DRISM-KH). All results were compared with known DprE1 inhibitors. Our studies suggest that four compounds (ChEMBL2441313, ChEMBL2338605, ChEMBL441373 and ChEMBL1607606) compounds may be explored as lead molecules for the rational drug designing of DprE1-inhibitors in MTB therapy.</p><br>

scholarly journals Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

2014 ◽  
Vol 10 ◽  
pp. 2789-2799 ◽  
Author(s):  
Bodee Nutho ◽  
Wasinee Khuntawee ◽  
Chompoonut Rungnim ◽  
Piamsook Pongsawasdi ◽  
Peter Wolschann ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Phenyl Ring ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Energy Prediction ◽  
Theoretical Approaches ◽  
Preferential Binding

In the present study, our aim is to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less binding or even unbinding preference was observed in the complexes where the larger chromone ring is located in the cavity. All MM- and QM-PBSA/GBSA free energy predictions supported the more stable fisetin/β-CD complex of the bound phenyl ring. Van der Waals interaction is the key force in forming the complexes. In addition, the quantum mechanics calculations with M06-2X/6-31G(d,p) clearly showed that both solvation effect and BSSE correction cannot be neglected for the energy determination of the chosen system.

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