IN SILICOSCREENING AND MOLECULAR DYNAMIC SIMULATION STUDIES OF POTENTIAL SMALL MOLECULE IMMUNOMODULATORS OF THE KIR2DS2 RECEPTOR

Abstract

The World Health Organization reports that cancer is one of the most common causes of death worldwide and it accounted for an estimated 9.6 million deaths in 2018. As compared with chemotherapy or radiotherapy, immunotherapy offers a safer, less stressful and selective strategy in the destruction of cancer cells. 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 with KIR2DS2 and possible bioactivity. A library of small molecule natural compounds obtained from edible African plants was used for in Silico molecular docking simulations of KIR2DS2 (PDBID: 1m4k) using Pyrx. An arbitrary docking score ≥ -7.0 kcal/mol was chosen as cut off value. 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 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. IntroductionThe Killer cell immunoglobulin-like receptors (KIRs) are usually located on a sub set of T cells and NK cells. These proteins are coded for by the polymorphic KIR genes, which translate into both activating (aKIR) and inhibiting (iKIR) receptors [1]. The KIR proteins are categorized according to the length of the cytoplasmic domains (short or long) they have or the quantity of extracellular domains (2D or 3D) they possess. The long cytoplasmic domains trigger inhibitory signals through the immune tyrosine-based inhibition motif (ITIM) as compared with the short cytoplasmic domains which trigger activating signals through the immune tyrosine-based activation motif (ITAM) [2]. Like other aKIRs, KIR2DS2 has two functional domains namely: Ig-like C2 type 1 and Ig-like C2 type 2 domains spanning from residues 42-107 and 142-205 respectively. Within these functional domains, KIR2DS2 differs from KIR2DL2 (an inhibitory receptor) with only three residues Tyrosine 45, Arginine 148, and Threonine 200; while it differs from KIR2DL3 (an inhibitory receptor) at only one residue: Tyrosine 45. Tyrosine 45 and Glutamine 71 prevents the recognition of HLA-C ligands by KIR2DS2. KIR2DS2 transduce signals through the TYRO protein tyrosine kinase binding protein (DAP12), Zeta-chain associated protein kinase (ZAP70)and Spleen tyrosine kinase (syk) mo...

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