Mudassir Khan, James N. Furze (2022) Cancer drug designing. 7 ºÝºÝߣ Presentation with oral commentary.pptx
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The document discusses designing novel cancer drug inhibitors through in silico modeling. It focuses on designing inhibitors for the SHP2 protein, which plays a role in cancer cell growth. Molecular docking was used to model interactions between potential inhibitor compounds and the SHP2 target. One novel organometallic compound (NIC2) showed increased specificity and stronger binding affinity compared to other compounds based on its docking energy of -12.47 kcal/mol. Protein-ligand interaction profiles were analyzed to understand binding between the best inhibitor and SHP2. The study demonstrates an in silico approach for identifying potential targeted cancer therapeutics.
![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](https://image.slidesharecdn.com/mudassirkhanjamesn-220915165327-c109b203/85/Mudassir-Khan-James-N-Furze-2022-Cancer-drug-designing-7-ºÝºÝߣ-Presentation-with-oral-commentary-pptx-5-320.jpg)
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Mudassir Khan, James N. Furze (2022) Cancer drug designing. 7 ºÝºÝߣ Presentation with oral commentary.pptx
- 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 ¨C ¡®organic¡¯ (-7.00 binding energy); b) NIC2 increased specificity ¨C ¡®organometallic¡¯ (-12.47 binding energy) Fig. 5 Protein preparation for docking - methodology flow (RCSB PBD ¨C 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. ------------------------------------------------------------------------------------------------------------------------------------------------------------- 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 ¨C 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
Editor's Notes
- #3: Pollution and saturation of the environment with complexes of chemical diversity result in the presence of carcinogens. The impact of carcinogenic molecules effect a range of disorders and diseases including cancers. Naturally prevention is better than cure, though the prolific modular spread of effected domains of proteins has evoked different treatments to lessen the cancerous spread.
- #4: Surgery, chemotherapy and radiotherapy are invasive techniques which counter cancer, though often result in death of the infected hosts. Targeted therapy and drug resistance lead research, though molecular-intracellular mechanisms largely remain unknown. Genetically, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is associated with leukaemia, breast, liver, lung, laryngeal, gastric, oral and other cancer types. Blocking of SHP2 causes senescence and arrests cancer growth. Designing a novel inhibitory compound (NIC) to bind to SHP2 inhibits its activity.
- #5: The design may be made using chemical simulation and sequencing software tools; its binding energy, inhibition constant, and precise interactive location and aspect may be determined using bioinformatics. Interactions will be explored using a protein ligand interaction profiler (PLIP). Further target verification maybe carried out using cell cultures.
- #6: NIC and SHP2 possible binding was verified, binding energy was determined and interactions were explored using PLIP.
- #7: Molecular docking software provided potential binding and energy, secondary screening will be carried out using cell cultures, cell viability assays and molecular techniques. In vivo disease modelling will reveal the minimum inhibitory concentration (MIC) and achieve a profile of inhibitory concentrations in biological systems. Application of generative and functional mathematics may be employed to provide further confirmation.