Molecular modeling and docking of small molecule inhibitors against NEK2

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.

Molecular Docking, 3D Structure-Based Pharmacophore Modeling, and ADME Prediction of Alpha Mangostin and Its Derivatives against Estrogen Receptor Alpha

“…While estradiol as a hERα agonist has a hydrogen bonding interaction with His524. 22 The design of the α-mangostin derivatives was focused on the modification of methoxy groups and dihydroxy substituted aromatic rings, 3-methylbut-2-enyl groups, and also based on the principal interaction between 4-OHT and hERα. The design of structural modification also considers the Lipinski rule or known as Lipinski's Rule of Five regarding the active compound administered orally and this rule establishes four physicochemical parameters (molecular weight ≤ 500, log P ≤ 5, donor hydrogen bond ≤ 5, and acceptor hydrogen bond ≤ 10) associated with 90% of the active drug administered orally that has reached clinical bic interactions.…”

“…These physicochemical parameters relate to acceptable solubility and permeability of the intestinal tract and are part of the early stages that determine oral bioavailability. 22 The structure of the hERα protein has a hydrogen bond on its constituent amino acid residues that is between Glu419 with His524 and Glu419 with Lys531 (hydrogen bond network). The disturbance of this hydrogen bonds network can be represented by fluctuations by a ligand has potential as an antagonist against hERα receptors.…”

Screening the binding potential of quercetin with parallel, antiparallel and mixed G-quadruplexes of human telomere and cancer protooncogenes using molecular docking approach

“…All the structure files for Parallel, Mixed and Anti-Parallel were curated from the Protein Data Bank (PDB) and were processed by the removal of excess unwanted waters and cations beyond 5 Angstroms from Hetro groups using Maestro [42]. Missing hydrogens were added and bond orders were assigned to stabilize the raw structure files from PDB.…”

Molecular Dynamics Simulation Estrogen Receptor Alpha againts Andrographolide as Anti Breast Cancer

“…Ligan akan bersifat antagonis ketika tidak membentuk ikatan hidrogen dengan His524. 17,18 Hasil penelitian menunjukkan bahwa andrografolid dan modifikasi strukturnya tidak membentuk ikatan hidrogen dengan asam amino His524 sehingga dapat dikatakan memiliki aktivitas antagonis seperti halnya tamoxifen yang juga tidak membentuk ikatan hidrogen dengan asam amino His524 pada helix-11.…”