Page 103 - Pharma News Letter - Vol2 Issue 1

Research Publications

Inhibition Of Colorectal Cancer Targets Il-6, Ctla-4, & B7-2 By
Tislelizumab: Molecular Docking, Dynamics, & String Protein-
Protein Network Analysis

Informatics In Medicine Unlocked. 2023; 41: 101323.
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Mahmoud Elkazzaz, Shahid Ullah, Tianshun Gao, Israa M. Shamkh, Amr Ahmed,
Ted X. Wu G, Maii S. Elsharayidi, Mohammad Shahbaz Khan, Aziz-Ur Rehman,

Marwa M. Lotfy, Abdullah Haikal, Mahmoud Abdalrahman

Abstract

As a DNA mismatch repair deficit (dMMR) anticancer medication, and a humanized monoclonal
antibody (hmAb), Tislelizumab has attracted significant interest in recent years. The programmed
cell death protein-1 (PD-1) and its ligands (PD-L1/CD274/B7-H1 and PDL2/CD273) may
bind to each other with great affinity. This binding prevents activated T-cells from continuing
to proliferate, produce cytokines, and engage in cytotoxic action. The B7:PD-1 inhibitory
immunological checkpoint receptor binds to the B7-2(CD86) B-lymphocyte activation antigen.
This paper presents Tislelizumab’s molecular docking and dynamics simulations with the
receptor B7-2(CD86) and its downstream signaling proteins CTLA-4 and IL-6. When docked
to B cell stimulatory factor-2 soluble IL-6 receptor alpha (sIL6Ra/CD126), Tislelizumab had
a strong binding affinity of 329 kcal/mol and provided an excellent quality model with an
LGscore of 4.54. The type I membrane protein B7-2(CD86), a member of the immunoglobulin
superfamily, responded to docking with an affinity of −332.35 kcal/mol and LGscore of 2.54.
Docking to the immune checkpoint protein receptor cytotoxic T-lymphocyte-associated protein-4
(CTLA-4/CD152) had a binding affinity of −305.91 kcal/mol, facilitating immunological
control and cellular dissociation. Tislelizumab and these target proteins exhibited persistent
and advantageous interactions in molecular dynamics studies. The STRING functional protein-
protein network analysis supported our in silico docking and dynamic simulation results. This
analysis also included comparisons of the binding modes of mAbs to protein receptors involved
in the cancer hallmark mechanism(s), demonstrating that IL-6, B7-2, and CTLA-4 act and are
inhibited in group-mode. Functional enrichment analysis and molecular modelling supported
the relationship between the hallmarks of the tumor microenvironment that link inflammation to
immunity. Tislelizumab may therefore be able to prevent these three proteins from acting. These
findings may also shine light on Dostarlimab’s mode of action, which in 2022 achieved ground-
breaking success in a clinical study for colorectal cancer.

Reference:

https://doi.org/10.1016/
j.imu.2023.101323

Vol. 2 - Issue 1 103