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Deep Learning and Structure-Based Virtual Screening for Drug Discovery against NEK7: A Novel Target for the Treatment
Mubashir Aziz1, Syeda Abida Ejaz1, Seema Zargar2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
Abstract:
NIMA-related kinase7 (NEK7) plays a multifunctional role in cell division and NLRP3 inflammasone activation. A typical expression or any mutation in the genetic makeup of NEK7 leads to the development of cancer malignancies and fatal inflammatory disease, i.e., breast cancer, non-small cell lung cancer, gout, rheumatoid arthritis, and liver cirrhosis. Therefore, NEK7 is a promising target for drug development against various cancer malignancies. The combination of drug repurposing and structure-based virtual screening of large libraries of compounds has dramatically improved the development of anticancer drugs. The current study focused on the virtual screening of 1200 benzene sulphonamide derivatives retrieved from the PubChem database by selecting and docking validation of the crystal structure of NEK7 protein (PDB ID: 2WQN). The compounds library was subjected to virtual screening using Auto Dock Vina. The binding energies of screened compounds were compared to standard Dabrafenib. In particular, compound 762 exhibited excellent binding energy of -42.67 kJ/mol, better than Dabrafenib (-33.89 kJ/mol). Selected drug candidates showed a reactive profile that was comparable to standard Dabrafenib. To characterize the stability of protein-ligand complexes, molecular dynamic simulations were performed, providing insight into the molecular interactions. The NEK7-Dabrafenib complex showed stability throughout the simulated trajectory. In addition, binding affinities, pIC50, and ADMET profiles of drug candidates were predicted using deep learning models. Deep learning models predicted the binding affinity of compound 762 best among all derivatives, which supports the findings of virtual screening. These findings suggest that top hits can serve as potential inhibitors of NEK7. Moreover, it is recommended to explore the inhibitory potential of identified hits compounds through in-vitro and in-vivo approaches.
Insights
NIMA-related kinase 7 (NEK7) is crucial for cell division and inflammation; targeting it with novel benzene sulfonamide derivatives shows promise for developing new cancer and inflammatory disease drugs.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Computational Drug Discovery
Background:
- NIMA-related kinase 7 (NEK7) is implicated in cell division and NLRP3 inflammasome activation.
- Dysregulation of NEK7 is linked to cancers (e.g., breast, lung) and inflammatory diseases (e.g., gout, rheumatoid arthritis, liver cirrhosis).
- NEK7 presents a viable therapeutic target for developing novel anticancer and anti-inflammatory agents.
Purpose of the Study:
- To virtually screen benzene sulfonamide derivatives as potential NEK7 inhibitors.
- To identify novel drug candidates for treating NEK7-associated malignancies and inflammatory conditions.
- To validate findings using molecular dynamics simulations and deep learning predictions.
Main Methods:
- Structure-based virtual screening of 1200 benzene sulfonamide derivatives against NEK7 (PDB ID: 2WQN) using Auto Dock Vina.
- Comparison of binding energies with the standard drug Dabrafenib.
- Molecular dynamic simulations to assess protein-ligand complex stability.
- Deep learning models for predicting binding affinity, pIC50, and ADMET profiles.
Main Results:
- Compound 762 demonstrated superior binding energy (-42.67 kJ/mol) compared to Dabrafenib (-33.89 kJ/mol).
- Selected drug candidates exhibited comparable reactivity profiles to Dabrafenib.
- Molecular dynamics simulations confirmed the stability of the NEK7-Dabrafenib complex.
- Deep learning models corroborated virtual screening results, identifying compound 762 as a top candidate.
Conclusions:
- Benzene sulfonamide derivative 762 is a promising NEK7 inhibitor candidate.
- The identified compounds warrant further investigation through in vitro and in vivo studies.
- This study highlights the potential of drug repurposing and virtual screening for NEK7-targeted therapies.
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