Keywords: carcinogens; cancer; targeted; SHP2; blocking

1. Cancer drug designing; in silico outcomes eliciting in vitro analysis
Mudassir Khan1,2,3, James N. Furze4,5
1 Department of Healthcare Biotechnology, National University of Sciences and Technology (NUST), Pakistan. 2 Chattha BioCare,
National University of Sciences and Technology (NUST), Pakistan. 3 Abdul Wali Khan University Mardan (AWKUM), Pakistan. 4
Laboratory of Biotechnology and Valorization of Natural Resources, Ibn Zohr University, Morocco. 5 Control and Systems
Engineering Department, University of Technology-Iraq, Iraq

2. Fig. 1 Environmental exposure risks from the air water and land with health risks (Trivedi et al. 2022)

3. Pro-Senescence therapy
SHP2
Oncogenic pathways
Inhibitor
Senescence
Cancer growth arrest
Cancer cells
SHP2
Senescence
Cancer growth
Oncogenic pathways
Fig. 2 Invasive techniques used to treat cancer Fig. 3 Targeted therapy to treat cancer: a) Structure of target SHP2; b) cancer
growth flow; c) inhibition of SHP2 arrests cancer growth (Kerr et al. 2021; Liu et
al. 2021; Song et al. 2022)
a
b c
Chemotherapy
Killing cancer cells
by agents
Radiotherapy
Killing cancer cells by
applying radiation
Surgery
Removal of tumour by
surgical methods

4. Protein
Preparation
Downloaded from
RCSB PDB
Auto Dock
Input file;
PDB format
Input file;
SYBYL MOL2
format
Ligand Synthesis
Molecular formula
ChemSketch
Ligand/Protein
preparation for
Docking
Fig. 4 Novel Inhibitory Compound designs: a) NIC1 low
specificity – ‘organic’ (-7.00 binding energy); b) NIC2 increased
specificity – ‘organometallic’ (-12.47 binding energy)
Fig. 5 Protein preparation for docking - methodology flow (RCSB PBD – Research
Collaboratory for Structural Bioinformatics Protein Data Bank)
a
b

5. Compound Target Binding Energy Inhibition constant (pM)
Novel inhibitor SHP2 -12.47 kcal/mol 725.25
Table 1 Binding energy of novel compound and target (SHP2)
Table 2 Hydrophobic interactions between SHP2 and NIC
Index Residue AA Distance H-A Distance D-A Donor
Angle
Donor Atom Acceptor
Atom
1 4A ARG 2.67 3.63 161.11 30 [Ng+] 4904 [N3]
2 4A ARG 3.06 3.93 147.64 31 [Ng+] 4904 [N3]
3 58A ASN 1.83 2.69 145.83 4932
[O.co2]
557 [O2]
4 63A TYR 2.53 3.29 135.63 613 [O3] 4904 [N3]
5 63A TYR 2.59 3.29 124.05 4904 [N3] 613 [O3]
6 507A THR 2.49 3.22 132.22 4710 [O3] 4931 [O.co2]
Index Residue AA Distance Ligand Atom Protein Atom
1 33A PRO 3.30 4912 318
2 38A PRO 3.04 4927 365
3 41A LEU 3.29 4917 388
4 508A GLU 3.58 4920 4717
Ligand
Protein
Salt bridge
Hydrogen Bond
Hydrophobic
interactions
Table 3 Hydrogen bonds between SHP2 and NIC
Fig. 6 Protein ligand interaction profile
(PLIP) of novel compound and target protein

7. Acknowledgments
We graciously acknowledge the support of Aftab Ahmad PhD, CEO of Chattha BioCare, National Sciences and Technology Park, National
University of Sciences and Technology for his advice and collaboration during early stages of the research.
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References
• Kerr DL, Haderk F, Bivona TG (2021) Allosteric SHP2 inhibitors in cancer: targeting the intersection of RAS, resistance, and the immune
microenvironment. Curr Opin Chem Biol 62:1-12. https://doi.org/10.1016/j.cbpa.2020.11.007
• Liu C, Lu H, Wang H et al (2021) Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin
Cancer Res 27(1):342-354. https://doi.org/10.1158/1078-0432.CCR-20-2718
• Song Y, Zhao M, Zhang H et al (2022) Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical
trials. Pharmacol Ther 107966. https://doi.org/10.1016/j.pharmthera.2021.107966
• Trivedi MH, Priyadarshi GV, Lalwani D et al (2022) Risk assessment applications – exposure, safety and security. In: Furze JN, Eslamian S,
Raafat SM, Swing K (eds) Earth systems protection and sustainability, vol 2. Springer, Cham. https://doi.org/10.1007/978-3-030-98584-4