Molecular modeling and docking of small molecule inhibitors against NEK2
Balaji Ramachandran1, Sabitha Kesavan1, Thangarajan Rajkumar1
1Department of Molecular Oncology, Cancer Institute (W.I.A), No.38, Sardar Patel Road, Adyar, Chennai - 600 036.
Abstract:
Aberrant expression of NEK2 (NIMA-related kinase 2) is indicated in a wide variety of human cancers. NEK2 is highly correlated to multi drug resistance by activating drug efflux activity. Identification of new small molecule inhibitors targeted against NEK2 therefore, facilitates to increase drug sensitivity of cancer cells, by stabilizing drug influx and minimizes the dose of therapeutic drug. Our work investigates to screen for optimal small molecule inhibitors against NEK2. In this study, we used a computational approach by modeling NEK2 protein using I-TASSER (Iterative Threading ASSEmbly Refinement) software. The modeled structure was subjected to protein preparation wizard; to add hydrogens and to optimize the protonation states of His, Gln and Asn residues. Active site of the modeled protein was identified using SiteMap tool of Schrodinger package. We further carried out docking studies by means of Glide, with various ligands downloaded from EDULISS database. Based on glide score, potential ligands were screened and their interaction with NEK2 was identified. The best hits were further screened for Lipinski's rule for drug-likeliness, bioactivity scoring and ADME properties. Thus, we report two (didemethylchlorpromazine and 2-[5-fluoro-1Hindol- 3-yl] propan-1-amine) compounds that have successfully satisfied all in silico parameters, necessitating further in vitro and in vivo studies.
Insights
Researchers identified two potential small molecule inhibitors for NEK2 (NIMA-related kinase 2) to combat cancer drug resistance. These compounds may enhance cancer cell drug sensitivity and reduce therapeutic doses.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Aberrant expression of NIMA-related kinase 2 (NEK2) is prevalent in various human cancers.
- NEK2 promotes multi-drug resistance in cancer cells by enhancing drug efflux.
- Targeting NEK2 is a strategy to improve cancer chemotherapy sensitivity and reduce drug dosage.
Purpose of the Study:
- To computationally screen for novel small molecule inhibitors targeting NEK2.
- To identify compounds that can potentially overcome NEK2-mediated drug resistance.
- To lay the groundwork for further in vitro and in vivo validation of NEK2 inhibitors.
Main Methods:
- 3D protein structure modeling of NEK2 using I-TASSER.
- Protein preparation and active site identification using Schrodinger's SiteMap.
- Molecular docking of ligands from the EDULISS database against NEK2 using Glide.
- In silico screening of top-scoring compounds for drug-likeness (Lipinski's rule) and ADME properties.
Main Results:
- Two compounds, didemethylchlorpromazine and 2-[5-fluoro-1H-indol-3-yl]propan-1-amine, were identified as promising NEK2 inhibitors.
- These compounds demonstrated favorable interactions with the NEK2 active site based on docking scores.
- The selected compounds met established in silico criteria for drug-likeness and pharmacokinetic properties.
Conclusions:
- Didemethylchlorpromazine and 2-[5-fluoro-1H-indol-3-yl]propan-1-amine are potential candidates for NEK2-targeted cancer therapy.
- These findings warrant further experimental validation through in vitro and in vivo studies.
- Computational screening provides an efficient approach for identifying novel anti-cancer drug leads against NEK2.
