Molecular modeling and identification of novel glucokinase activators through stepwise virtual screening.
The glucose phosphorylating enzyme glucokinase (GK) is a 50kD monomeric protein having 465 amino acids. It maintains glucose homeostasis inside cells, acts as a glucose sensor in pancreatic β-cells and as a rate controlling enzyme for hepatic glucose clearance and glycogen synthesis. It has two binding sites, one for binding d-glucose and the other for a putative allosteric activator named glucokinase activator (GKA). The GKAs interact with the same region of the GK enzyme that is commonly affected by naturally occurring mutations in humans. However, many GKAs do not bind to GK in the absence of glucose. Recently, it has been reported that GKAs are highly effective in patients with type 2 diabetes mellitus. In this milieu a molecular modeling study has been carried out on three natural variants of GK that lie in the GKA binding site and are known to cause maturity onset diabetes of young (MODY). Additionally, a 10ns molecular dynamics simulation was done on each of the modeled variant in order to explore the flexibility of this site. Subsequently, a systematic virtual screening study was done to identify compounds which can bind with high affinity at GKA binding site of mutant GK.
Centre of Biotechnology, Siksha O Anusandhan University, Bhubaneswar, 751030, Odisha, India.
Pabitra Mohan
PM
Behera
Centre of Biotechnology, Siksha O Anusandhan University, Bhubaneswar, 751030, Odisha, India.
Deepak Kumar
DK
Behera
Institute of Life Sciences, Nalco Square, Bhubaneswar, 751023, Odisha, India.
Suresh
S
Satpati
Institute of Life Sciences, Nalco Square, Bhubaneswar, 751023, Odisha, India.
Geetanjali
G
Agnihotri
Centre of Biotechnology, Siksha O Anusandhan University, Bhubaneswar, 751030, Odisha, India.
Sanghamitra
S
Nayak
Research and Development Centre, Hi-Tech Medical College and Hospital, Bhubaneswar, 751025 Odisha, India.
Payodhar
P
Padhi
Institute of Life Sciences, Nalco Square, Bhubaneswar, 751023, Odisha, India. Electronic address: anshumandixit@gmail.com.
Anshuman
A
Dixit
D000495:Allosteric Site; D004353:Drug Evaluation, Preclinical; D020536:Enzyme Activators / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D014584:User-Computer Interface
D020536:Enzyme Activators; D005941:Glucokinase
Diabetes; Glucokinase; Glucokinase activator; Molecular docking; Molecular dynamics simulation; Virtual screening