Ligand‐Based Pharmacophore Mapping and Virtual Screening for the Search of Biguanide‐Like Molecules With Antidiabetic Potentials Targeting Liver Kinase B1

Type 2 diabetes mellitus (T2DM) is a state where the body’s glucose metabolism is compromised. AMP‐activated protein kinase, or AMPK, has an important part to play in glucose metabolism, and the liver kinase B1 (LKB1) protein functions as a major upstream kinase for AMPK activation, thereby making it appealing therapeutic targets for treating and preventing T2DM. Drug resistance cases for biguanides like metformin is a serious concern and pose great threat to treatment success for diabetic patients. Thus, the hunt for biguanide‐like small molecules with enhanced insulin sensitizing potentials is necessary. In the present study, interaction between LKB1 and biguanides such as phenformin, metformin, and buformin has been thoroughly assessed using computational tools. Ligand‐based pharmacophore mapping of 29,000 phytochemicals collected from NPASS database was carried out. The screening was conducted to hunt novel antidiabetic compounds targeting LKB1 pathway to improve insulin sensitivity in T2DM. Molecular docking of 31 phytochemicals with good pharmacophore fit scores was then carried out to identify hit compounds. ADMET analysis was also utilized to screen down compounds. dragmacidin D, dioncopeltine A, saussureamine C, and agelastatin D have good binding affinities and acceptable ADMET parameters. Molecular dynamics simulation was carried out to confer the stability of ligand–protein complex under simulated human body conditions. After 100 nanoseconds molecular dynamics simulation, the LKB1 protein complexed with compounds (saussureamine C and agelastatin D) was found to be stable. The results of the current study can be useful in developing antidiabetic medications with enhanced insulin sensitization activates superior to those available in market.