Abstract
Homeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtual screening study is presented to filter novel strong CCR7 binding phytochemicals from Saudi medicinal plants that have a higher binding affinity for the intracellular allosteric binding pocket. By doing so, three small natural molecules named as Hit-1 (1,8,10-trihydroxy-3-methoxy-6-methylanthracen-9(4H)-one), Hit-2 (4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one), and Hit-3 (10-methyl-12,13-dihydro-[1,2]dioxolo[3,4,5-de]furo[3,2-g]isochromeno[4,3-b]chromen-8-ol) are predicted showing strong binding potential for the CC chemokine receptor 7 allosteric pocket. During molecular dynamics simulations, the compounds were observed in the formation of several chemical bonding of short bond distances. Additionally, the molecules remained in strong contact with the active pocket residues and experienced small conformation changes that seemed to be mediated by the CCR7 loops to properly engage the ligands. Two types of binding energy methods (MM/GBPBSA and WaterSwap) were additionally applied to further validate docking and simulation findings. Both analyses complement the good affinity of compounds for CCR7, the electrostatic and van der Waals energies being the most dominant in intermolecular interactions. The active pocket residue’s role in compounds binding was further evaluated via alanine scanning, which highlighted their importance in natural compounds binding. Additionally, the compounds fulfilled all drug-like rules: Lipinski, Ghose, Veber, Egan, and Muegge passed many safety parameters, making them excellent anti-cancer candidates for experimental testing.
Highlights
The human immune system has the potential to fight against pathogens without harming normal cells and tissues
Chemotactic trafficking is regulated by 20 G protein-coupled receptors (GPCRs) and more than 40 chemokines
Computer-aided drug design is gaining popularity to virtually screen small drug molecule libraries against a given biological time, saving time and economic losses associated with experimental drug design
Summary
The human immune system has the potential to fight against pathogens without harming normal cells and tissues. Inflammatory chemokines and receptors are generated in response to inflammatory stimuli, whereas homeostatic chemokines are produced continuously, which direct cells to certain organs [2]. Chemokine ligands such as CCL19 and CCL21 bind the CC chemokine receptor 7 (CCR7) to direct B cells, T cells, and dendritic cells to lymph nodes all across the body. The chemotactic trafficking creates cellular pathways, wherein the inflammatory immune response is induced by inflammation chemokines and target specific cells. CCL19 and CCL21 are the cellular cation receptors that, when attached to CCR7, navigate cellular and humoral immunity along with dendritic cells toward the host lymph system [3]
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