In silico screening and molecular dynamic simulation studies of potential small molecule immuno-modulators of the KIR2DS2 receptor

Abstract

Cancer is reported to be one of the most common causes of global deaths and it accounted for an estimated 9.6 million fatalities in 2018. Immunotherapy destroys cancer cells with mechanisms of action considered to be safer and with greater precision than chemotherapy or radiotherapy. The killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) expressed on Natural Killer (NK) cells are involved in signal transduction processes that produce pro-inflammatory cytokines and directly destroy cancer and virally infected cells. The aim of this study is to identify small molecules from natural products that have strong binding affinity to KIR2DS2 and to predict possible nuclear receptor ligand bioactivity. A library of small molecule natural compounds obtained from edible African plants was used for in silico molecular docking simulations of the human natural killer cell activator receptor KIR2DS2 (PDBID: 1m4k) using PyRx. Only compounds with binding affinity stronger than that elicited by the target and the standard, N-acetyl-D-glucosamine were selected. Screening for drug-likeness and ligand efficiency was based on the molecular descriptors of the compounds as provided by PubChem. Further screening for saturation, molar refractivity, promiscuity, pharmacokinetic properties, and bioactivity was done using SWISSADME, PKCSM, and Molinspiration webservers respectively. The molecular dynamic simulation and analyses was done using the Galaxy webserver which uses the GROMACS software. Analyses of molecular dynamic simulation were done using Galaxy and MDWEB webservers. Gibberellin A20 and A29 were obtained as the lead compounds, and they show better promise as drug candidates for KIR2DS2 than the standard. It is recommended that the immuno-stimulatory effect of the lead compounds on KIR2DS2 be further investigated.