title: Investigation on the isoform selectivity of novel kinesin-like protein 1 (KIF11) inhibitor using chemical feature based pharmacophore, molecular docking, and quantum mechanical studies.
abstract: Kinesin-like protein (KIF11) is a molecular motor protein that is essential in mitosis. Removal of KIF11 prevents centrosome migration and causes cell arrest in mitosis. KIF11 defects are linked to the disease of microcephaly, lymph edema or mental retardation. The human KIF11 protein has been actively studied for its role in mitosis and its potential as a therapeutic target for cancer treatment. Pharmacophore modeling, molecular docking and density functional theory approaches was employed to reveal the structural, chemical and electronic features essential for the development of small molecule inhibitor for KIF11. Hence we have developed chemical feature based pharmacophore models using Discovery Studio v 2.5 (DS). The best hypothesis (Hypo1) consisting of four chemical features (two hydrogen bond acceptor, one hydrophobic and one ring aromatic) has exhibited high correlation co-efficient of 0.9521, cost difference of 70.63 and low RMS value of 0.9475. This Hypo1 is cross validated by Cat Scramble method; test set and decoy set to prove its robustness, statistical significance and predictability respectively. The well validated Hypo1 was used as 3Dquery to perform virtual screening. The hits obtained from the virtual screening were subjected to various scrupulous drug-like filters such as Lipinski's rule of five and ADMET properties. Finally, six hit compounds were identified based on the molecular interaction and its electronic properties. Our final lead compound could serve as a powerful tool for the discovery of potent inhibitor as KIF11 agonists.
authors.affiliation: Dept. of Physics, G.K.M. College of Engineering & Technology, Alapakkam, Mappedu Road, Perungalathur, Tamil Nadu 600 063, India.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Karunagaran
authors.affiliation: Centre for Research and Development, Prist University, Vallam, Thanjavur, Tamil Nadu 621 316, India.
authors.forename: Subramaniyan
authors.initials: S
authors.lastname: Subhashchandrabose
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju 660-701, Republic of Korea.
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Dept. of Physics, G.K.M. College of Engineering & Technology, Alapakkam, Mappedu Road, Perungalathur, Tamil Nadu 600 063, India. Electronic address: megac2005@gmail.com.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Meganathan
mesh_terms: D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D056004:Molecular Dynamics Simulation; D020033:Protein Isoforms / Q000378:metabolism*; D011789:Quantum Theory; D013329:Structure-Activity Relationship
chemical_list: D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; C087665:kinesin-like protein 1
keywords: Density functional theory; Kinesin like protein-1; Molecular docking; Pharmacophore modeling