title: Pharmacophore modeling, virtual screening, molecular docking studies and density functional theory approaches to identify novel ketohexokinase (KHK) inhibitors.
abstract: Fructose catabolism starts with phosphorylation of d-fructose to fructose 1-phosphate, which is performed by ketohexokinase (KHK). Fructose metabolism may be the key to understand the long-term consumption of fructose in human's obesity, diabetes and metabolic states in western populations. The inhibition of KHK has medicinally potential roles in fructose metabolism and the metabolic syndrome. To identify the essential chemical features for KHK inhibition, a three-dimensional (3D) chemical-feature-based QSAR pharmacophore model was developed for the first time by using Discovery Studio v2.5 (DS). The best pharmacophore hypothesis (Hypo1) consisting two hydrogen bond donor, two hydrophobic features and has exhibited high correlation co-efficient (0.97), cost difference (76.1) and low RMS (0.66) value. The robustness and predictability of Hypo1 was validated by fisher's randomization method, test set, and the decoy set. Subsequently, chemical databases like NCI, Chembridge and Maybridge were screened for validated Hypo1. The screened compounds were further analyzed by applying drug-like filters such as Lipinski's rule of five, ADME properties, and molecular docking studies. Further, the highest occupied molecular orbital, lowest unoccupied molecular orbital and energy gap values were calculated for the hits compounds using density functional theory. Finally, 3 hit compounds were selected based on their good molecular interactions with key amino acids in the KHK active site, GOLD fitness score, and lowest energy gaps.
authors.affiliation: Sri Ramanujar Engineering College, Kolapakkam, Vandalur 600 048, Tamil Nadu, India.
authors.forename: Rengarajan
authors.initials: R
authors.lastname: Kavitha
authors.affiliation: G.K.M College of Engineering and Technology, Alapakkam, Mappedu Road, Perungalathur, 600 063 Chennai, Tamil Nadu, India.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Karunagaran
authors.affiliation: Centre for Research and Development, PRIST University, Trichy-Thanjavur Road, Vallam 621 316, Tamil Nadu, India.
authors.forename: Subramaniam Subhash
authors.initials: SS
authors.lastname: Chandrabose
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: G.K.M College of Engineering and Technology, Alapakkam, Mappedu Road, Perungalathur, 600 063 Chennai, Tamil Nadu, India. Electronic address: megac2005@gmail.com.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Meganathan
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D005631:Fructokinases / Q000737:chemistry*; D008956:Models, Chemical; D062105:Molecular Docking Simulation / Q000379:methods*; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D005631:Fructokinases; C021475:ketohexokinase
keywords: Ketohexokinase; Molecular docking; Pharmacophore modeling; Virtual screening