In silico designing of hyper-glycosylated analogs for the human coagulation factor IX

Ghasemi, Fahimeh; Zomorodipour, Alireza; Karkhane, Ali Asghar; Khorramizadeh, Mohammadreza

doi:10.1016/j.jmgm.2016.05.011

Cited by 48 publications

(14 citation statements)

References 44 publications

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“…Radius of gyration (Rg) is used for the evaluation of the stability of complex biological systems by calculating the structural compactness of the biomolecules along the molecular dynamics trajectory [ 26 ]. We also used this parameter to confirm if the complexes were stably folded throughout the 20ns MD simulation and if the Rg are relatively consistent throughout the simulation, it is regarded as been stably folded [ 27 ]. The graph represented as Figure 6 is a function of Rg with respect to the time of simulations for both the Keap1 protein and the complexes (Keap1-MASA, Keap1-18-AGA and Keap1-RES).…”

Section: Resultsmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

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Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

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Section: Resultsmentioning

confidence: 99%

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Adelusi

Abdul-Hammed

Idris

et al. 2021

Heliyon

View full text Add to dashboard Cite

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“…Furthermore, the average Rg values of Mpro-L1, Mpro-L2, Mpro-L3 and Mpro-L4 complex were 1.8 ± 0.07 nm, 1.8 ± 0.07 nm, 1.9 ± 0.06 nm, and 1.8 ± 0.08 nm respectively, which is significantly similar as compared to reference 1.8 ± 0.08 nm molecule ( Figure 7 ). As stated earlier, If protein will likely maintain a relatively steady value of Rg throughout the MD simulation it can be regarded as stably folded, and if its Rg changed over time, it would be considered unfolded (Ghasemi et al., 2016 ). As a result, it can be observed, that each complex exhibited relatively similar behavior of compactness and consistent values of Rg as compared to the native and reference.…”

Section: Resultsmentioning

confidence: 99%

A dynamic simulation study of FDA drug from zinc database against COVID-19 main protease receptor

Mathpal

Joshi

Sharma

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The sudden outbreak of COVID-19 has been responsible for several deaths across the globe. Due to its high contagious nature, it spreads from one human to another very quickly. Now it becomes a global public health threat with no approved treatments. In silico techniques can accelerate the drug development process. Our research aimed to identify the novel drugs for inhibition of Main protease (Mpro) enzyme of COVID-19 by performing in silico approach. In this context, a library consisting of 3180 FDA-approved drugs from 'the ZINC database' was used to identify novel drug candidates against 'the Mpro' of SARS-CoV-2. Initially, the top 10 drugs out of 3180 drugs were selected by molecular docking according to their binding score. Among 10 selected drugs; seven drugs that showed binding with Mpro enzyme residue Glu166 were subjected to100 ns Molecular dynamics (MD) simulation. Out of seven compounds, four namely, ZINC03831201, ZINC08101052, ZINC01482077, and ZINC03830817 were found significant based on MD simulation results. Furthermore, RMSD, RMSF, RG, SASA, PCA, MMPBSA (for last 40 ns) were calculated for the 100 ns trajectory period. Currently, the world needs potent drugs in a short period and this work suggests that these four drugs could be used as novel drugs against COVID-19 and it also provides new lead compounds for further in vitro, in vivo, and ongoing clinical studies against SARS-CoV-2.

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“…RG is also used to check whether the complexes are stably folded or unfolded during the MD simulation. If the RG shows a relatively consistent value throughout the MD simulation, it can be regarded as a stably folded structure; otherwise, it would be considered an unfolded structure [ 33 ]. The RG plot for Mpro and all Mpro-ligand complexes is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Using Chou’s 5-steps rule to study pharmacophore-based virtual screening of SARS-CoV-2 Mpro inhibitors

Pundir

Joshi²,

Joshi

et al. 2020

Mol Divers

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Recently emerged SARS-CoV-2 is the cause of the ongoing outbreak of COVID-19. It is responsible for the deaths of millions of people and has caused global economic and social disruption. The numbers of COVID-19 cases are increasing exponentially across the world. Control of this pandemic disease is challenging because there is no effective drug or vaccine available against this virus and this situation demands an urgent need for the development of anti-SARS-CoV-2 potential medicines. In this regard, the main protease (Mpro) has emerged as an essential drug target as it plays a vital role in virus replication and transcription. In this research, we have identified two novel potent inhibitors of the Mpro (PubChem3408741 and PubChem4167619) from PubChem database by pharmacophore-based high-throughput virtual screening. The molecular docking, toxicity, and pharmacophore analysis indicate that these compounds may act as potential anti-viral candidates. The molecular dynamic simulation along with the binding free energy calculation by MMPBSA showed that these compounds bind to Mpro enzyme with high stability over 50 ns. Our results showed that two compounds: PubChem3408741 and PubChem4167619 had the binding free energy of − 94.02 kJ mol −1 and − 122.75 kJ mol −1 , respectively, as compared to reference X77 (− 76.48 kJ mol −1). Based on our work's findings, we propose that these compounds can be considered as lead molecules for targeting Mpro enzyme and they can be potential SARS-CoV-2 inhibitors. These inhibitors could be tested in vitro and explored for effective drug development against COVID-19. Hemlata Pundir and Tanuja Joshi have contributed equally to the work.

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In silico designing of hyper-glycosylated analogs for the human coagulation factor IX

Cited by 48 publications

References 44 publications

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors – An insight into the atomistic mechanisms of their antioxidant potential

A dynamic simulation study of FDA drug from zinc database against COVID-19 main protease receptor

Using Chou’s 5-steps rule to study pharmacophore-based virtual screening of SARS-CoV-2 Mpro inhibitors

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