Identification of novel discoidin domain receptor 1 (DDR1) inhibitors using E-pharmacophore modeling, structure-based virtual screening, molecular dynamics simulation and MM-GBSA approaches

Nada, Hossam; Lee, Kyeong; Gotina, Lizaveta; Pae, Ae Nim; Elkamhawy, Ahmed

doi:10.1016/j.compbiomed.2022.105217

Cited by 46 publications

(37 citation statements)

References 53 publications

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“…After successful validation, the library of compounds was imported and prepped into MOE database file, that was then docked using “Induced fit” protocol. The interactions were then viewed using Discovery Studio Visualizer 2021 [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Methodsmentioning

confidence: 99%

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management

et al. 2022

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Keratoconus (KC) is a serious disease that can affect people of any race or nationality, although the exact etiology and pathogenic mechanism are still unknown. In this study, thirty-two FDA-approved ophthalmic drugs were exposed to virtual screening using docking studies against both the MMP-2 and MMP-9 proteins to find the most promising inhibitors as a proposed computational mechanism to treat keratoconus. Matrix metalloproteinases (MMPs) are zinc-dependent proteases, and MMP inhibitors (MMPIs) are usually designed to interact with zinc ion in the catalytic (CAT) domain, thus interfering with enzymatic activity. In our research work, the FDA-approved ophthalmic medications will be investigated as MMPIs, to explore if they can be repurposed for KC treatment. The obtained findings of the docking study suggest that atenolol and ampicillin are able to accommodate into the active sites of MMP-2 and MMP-9. Additionally, both exhibited binding modes similar to inhibitors used as references, with an ability to bind to the zinc of the CAT. Molecular dynamic simulations and the MM-GBSA binding free-energy calculations revealed their stable binding over the course of 50 ns. An additional pharmacophoric study was carried out on MMP-9 (PDB ID: 1GKC) using the co-crystallized ligand as a reference for the future design and screening of the MMP-9 inhibitors. These promising results open the door to further biological research to confirm such theoretical results.

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Section: Methodsmentioning

confidence: 99%

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management

et al. 2022

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“…These molecules were used to create a test set composed of 30 compounds ( Table S1 ). A structure-based hypothesis and ligand-protein complex-based hypotheses were developed and validated following the same protocol as described in our previous investigation in identifying novel DDR1inhibitors ( Nada et al, 2022b ).…”

Section: Methodsmentioning

confidence: 99%

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations

Nada

Elkamhawy

Lee

2022

PeerJ

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The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.

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“…Eventually, the compounds from XP were evaluated using the molecular mechanics with generalised born and surface area solvation (MM‐GBSA) approach to predict their free energies (ΔG bind ) during binding with the help of the Prime module. The pharmacokinetic properties of the substances passed through the filtration procedures were studied in greater depth 12,33 …”

Section: Methodsmentioning

confidence: 99%

“…The pharmacokinetic properties of the substances passed through the filtration procedures were studied in greater depth. 12,33…”

Section: Screening Of Potential Candidates and Mm/gbsa Calculationsmentioning

confidence: 99%

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Tayubi

2022

J of Cellular Biochemistry

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The mutations at the hotspot region of K‐Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K‐Ras model with anti‐cancerous activity from food and drug administration (FDA)‐approved drug compounds. We implemented several computational strategies such as pharmacophore‐based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K‐Ras. We found that the FDA‐approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K‐Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h‐bonds, and potent inhibition against G13D K‐Ras. As a result, the current research identifies prospective K‐Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K‐Ras‐driven cancers.

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Identification of novel discoidin domain receptor 1 (DDR1) inhibitors using E-pharmacophore modeling, structure-based virtual screening, molecular dynamics simulation and MM-GBSA approaches

Cited by 46 publications

References 53 publications

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management

Screening a Panel of Topical Ophthalmic Medications against MMP-2 and MMP-9 to Investigate Their Potential in Keratoconus Management

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

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