Molecular modeling on porphyrin derivatives as β5 subunit inhibitor of 20S proteasome

Arba, Muhammad; Nur-Hidayat, Andry; Ruslin, Ruslin; Yusuf, Muhammad; Sumarlin,; Hertadi, Rukman; Wahyudi, Setyanto Tri; Surantaadmaja, Slamet Ibrahim; Tjahjono, Daryono Hadi

doi:10.1016/j.compbiolchem.2018.03.002

Cited by 4 publications

(5 citation statements)

References 54 publications

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Section: Molecular Dynamics Studies To Investigate Dual-inhibitor Hits Produced From Molecular Dockingcontrasting

confidence: 79%

“…This is in line with the fact that CHEMBL3794075 stays closer to THR1 and, therefore, closer to this second set of residues. The level of fluctuation obtained in this work is significantly smaller than RMSF profiles reported for other inhibitors [52]. To assess the particular positioning of the two docking hits with respect to key Hbonding residues, we monitored the shortest distance between each compound and THR1 of the β5 chain of P20S, or HIS307 of EZH2.…”

Section: Molecular Dynamics Studies To Investigate Dual-inhibitor Hits Produced From Molecular Dockingmentioning

confidence: 84%

“…Zhang et al (2009) define it as a weak H-bonding residue owing to the low occurrence of bonding events for THR21 [53]. Additionally, LYS33 and TYR168 were reported to form H-bonds in MD simulations, and many other sparse (i.e., low occupancy) interactions to binding molecules have been identified, namely ASP114 and SER118 (β6) as well as ALA22, GLY23, TRP25, ARG165, and ASN208 (β5) [52]. Among these, we have observed contacts with ALA22 only, which was exclusively detected for CHEMBL3794075.…”

Section: Discussionmentioning

confidence: 99%

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Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds.

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Section: Molecular Dynamics Studies To Investigate Dual-inhibitor Hits Produced From Molecular Dockingcontrasting

confidence: 79%

Section: Molecular Dynamics Studies To Investigate Dual-inhibitor Hits Produced From Molecular Dockingmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

et al. 2021

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“…Molecular dynamics (MD) simulation of 100 ns was performed for Compound 12 (Comp12), RA1, RA2, RA3, and RA4, each complexed with EGFR. The details of MD protocol follow our previous work (Arba et al, 2018a). Molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA) (Kollman et al, 2000) calculation was performed to predict the binding free energy of Comp12, RA1, RA2, RA3 and RA4 to EGFR.…”

Section: Molecular Dynamics Simulation and Mm-pbsa Calculationmentioning

confidence: 99%

3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

2019

J App Pharm Sci

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To develop novel and more potent quinazoline-phosphoramidate mustard conjugates as epidermal growth factor receptor (EGFR) inhibitor, three-dimensional quantitative structure-activity relationship [comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)] combined with molecular docking were performed. A series of 13 compounds in the training set gave q 2 values of 0.577 and 0.537, as well as r 2 values of 0.926 and 0.921 for CoMFA and CoMSIA models, respectively. The contour maps that were produced by the CoMFA and CoMSIA models revealed that steric, electrostatic, and hydrophobic fields were crucial in the inhibitory activity of quinazoline-phosphoramidate derivatives. Based on the CoMFA and CoMSIA models, several novel EGFR inhibitors were designed, which established crucial interactions at the ligand binding domain of EGFR. Nearly, 100 ns MD simulation indicated the stability of the designed compounds at 100 ns, while molecular mechanics-Poisson Boltzmann surface area calculation showed that the designed compound had a higher affinity than that of the parent compound.

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“…Our last in silico protocol was the calculation of the binding free energy, which was performed using the Molecular Mechanics-Poisson Boltzmann solvent accessible surface area (MM-PBSA) method (Arba et al, 2018a;2018b;Kollman et al, 2000). The binding energy was calculated using 200 snapshots taken from 20 to 40 ns simulation trajectories with the python modules of AMBER16 (Miller et al, 2012).…”

Section: Binding Free Energy Calculationsmentioning

confidence: 99%

Computational approach toward targeting the interaction of porphyrin derivatives with Bcl-2

2018

J App Pharm Sci

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Bcl-2 protein has been identified as a potential therapeutic target of cancer. Many inhibitors which target the protein have been developed. Here, we investigated the interaction between porphyrin conjugated with anthraquinone group with a variation on meso substituent either pyrazolium or pyridine, and Bcl-2 using computational molecular docking and molecular dynamics simulation. Molecular docking was performed using AutoDock Vina, while molecular dynamics (MD) simulation of 50 ns was conducted using AMBER16. Our study indicates that the designed compounds interacted with crucial residues of Bcl-2 active site. Prediction of binding free energy by molecular mechanics-Poisson Boltzmann solvent accessible surface area method shows that mono-H 2 PzP-AQ has a comparable affinity with that of cognate ligand, 1XJ. Additionally, porphyrin binding was mainly supported by electrostatic and van der Waals energies.

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Molecular modeling on porphyrin derivatives as β5 subunit inhibitor of 20S proteasome

Cited by 4 publications

References 54 publications

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

Computational approach toward targeting the interaction of porphyrin derivatives with Bcl-2

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