Virtual structure-based docking and molecular dynamics of FDA-approved drugs for the identification of potential IKKB inhibitors possessing dopaminergic activity in Alzheimer’s disease

In Alzheimer's disease (AD), neuroinflammation is detrimental in causing neurodegeneration. In the central nervous system, inhibitor of nuclear factor kappa B kinase subunit beta (IKK2/IKKβ/IKKB/IKBKB) signaling is linked to neuroinflammation-mediated learning and memory deficits through canonical pathway, while dopamine agonists have been known to reverse such effects. Our in silico analysis predicted if dopaminergic agonists could have IKKB inhibitory actions, to ameliorate neuroinflammation-associated learning and memory deficits. Here, the FDA-approved Zinc 15 database was screened with IKKB (PDB ID 4KIK). Potential molecules with IKKB inhibition were identified through docking, which also possessed dopaminergic activity. Molecular mechanics—generalized Born and surface area (MMGBSA), induced fit docking (IFD) and molecular dynamic (MD) studies of 100 ns simulation time were done. Apomorphine and rotigotine showed greater non-bonding and bonding interactions with amino acids of IKKB as compared to Aripiprazole in docking studies. The IFD studies predicted improved interactions with IKKB. MMGBSA scores indicated that the complex binding free energies were favorable, and MD studies showed an acceptable root mean square deviation between protein and ligands. The protein–ligand interactions showed hydrogen bonds, water and salt bridges necessary for IKKB inhibition, as well as solvent system stability. On the protein–ligand contact map, the varying color band intensities represented the ligand’s ability to bind with amino acids. Dopamine agonists apomorphine, rotigotine, and aripiprazole were predicted to bind and inhibit IKKB in in silico system. Graphical Abstract: [Figure not available: see fulltext.]