PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA

Adasme, Melissa F.; Linnemann, Katja L; Bolz, Sarah Naomi; Kaiser, Florian; Salentin, Sebastian; Haupt, V. Joachim; Schroeder, Michael

doi:10.1093/nar/gkab294

Cited by 1,076 publications

(680 citation statements)

References 38 publications

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“…The docked pose of each ligand in both proteins was analysed using PLIP tools [ 47 ] to extract all established interactions with each target, and the obtained interaction profiles are shown in Figure 12 .…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…The PyMOL Molecular Graphics (Version 1.8.4.0, Schrödinger, LLC) was used for the visualizations and graphics generations [ 33 ]. To determine the interactions of all the docking complexes, the protein-ligand interaction profiler (PLIP) was used to analyze the crystal structure of the available structural complexes [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

Gao

Xin

et al. 2021

Molecules

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Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents.

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“…To validate the docking method, we applied it to other literature dockings having M pro as a protein target [47], and used the N3 inhibitor as a reference compound (Figure 2), finding that the resulting scores were in line with those previously reported for ligands like the phenolic diterpene carnosol [46], bictegravir, and other molecules docked to the same protease [48]. We made use of the molecular graphics program embedded in 1-Clik Mcule for structural visualization of protein-ligand complexes and to obtain the snapshots of Figure 3A,B, while we obtained the protein-ligand interaction diagrams reported in the same figure (Figure 3C,D) and in Figure 4 by ProteinsPlus (https://proteins.plus/) or PLIP (Protein-Ligand Interaction Profiler, https://plip-tool.biotec.tu-dresden.de/) [49,50]. For the N3 inhibitor/astragalin-bound M pro structural comparison (Figure 3E), we made use of the matchmaker tool embedded in UCSF Chimera [51].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

In Silico Investigation on the Interaction of Chiral Phytochemicals from Opuntia ficus-indica with SARS-CoV-2 Mpro

Vicidomini

Roviello

2021

Symmetry

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Opuntia ficus-indica is a cactaceous plant native to America but, nowadays, widely found worldwide, having been the most common domesticated species of cactus grown as a crop plant in semiarid and arid parts of the globe, including several Mediterranean basin countries. Opuntia ficus-indica can be regarded as a medicinal plant, being source of numerous bioactive phytochemicals such as vitamins, polyphenols, and amino acids. The urgent need for therapeutic treatments for the COronaVIrus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome (SARS)-Coronavirus (CoV)-2, justifies the great attention currently being paid not only to repurposed antiviral drugs, but also to natural products and herbal medications. In this context, the anti-COVID-19 utility of Opuntia ficus-indica as source of potential antiviral drugs was investigated in this work on the basis of the activity of some of its phytochemical constituents. The antiviral potential was evaluated in silico in docking experiments with Mpro, i.e., the main protease of SARS-CoV-2, that is one of the most investigated protein targets of therapeutic strategies for COVID-19. By using two web-based molecular docking programs (1-Click Mcule and COVID-19 Docking Server), we found, for several flavonols and flavonol glucosides isolated from Opuntia ficus-indica, good binding affinities for Mpro, and in particular, binding energies lower than −7.0 kcal/mol were predicted for astragalin, isorhamnetin, isorhamnetin 3-O-glucoside, 3-O-caffeoyl quinic acid, and quercetin 5,4′-dimethyl ether. Among these compounds, the chiral compound astragalin showed in our in silico studies the highest affinity for Mpro (−8.7 kcal/mol) and also a low toxicity profile, emerging, thus, as an interesting protease inhibitor candidate for anti-COVID-19 strategies.

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PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA

Cited by 1,076 publications

References 38 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

Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

In Silico Investigation on the Interaction of Chiral Phytochemicals from Opuntia ficus-indica with SARS-CoV-2 Mpro

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