Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. Construction and Dynamic Simulations of Biological Regulatory Network (BRN)
2.2. Ligand Data Collection & Rectification
2.3. Molecular Docking Simulations & Pose Analysis
3. Results
3.1. Biological Regulatory Network (BRN) Simulations of IP3R
3.1.1. Dynamic Model Simulation in Normal Cells
3.1.2. Dynamic Model Simulation in Cancer Cells
3.2. Data Set of IP3R Inhibitors and Structure Activity Relationship (SAR)
3.3. Pose Selection and Molecular Docking Simulations
3.4. Protein Ligand Interaction Fingerprints (PLIF) Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Nodes | In Normal Cell | In Cancer Cell | ||||||
---|---|---|---|---|---|---|---|---|
without IP3R Perturbation | with IP3R Perturbation | without Inhibitor | with Inhibitor | |||||
before Simulation | after Simulation | before Simulation | after Simulation | before Simulation | after Simulation | before Simulation | after Simulation | |
IP3R | 0.0 | 0.945 | 0.5 * | 0.393 | 1.0 | 1.0 | 1.0 * | 0.949 |
Ca+2 | 0.0 | 0.926 | 0.0 | 0.333 | 0.0 | 0.99 | 0.9 | 0.951 |
CALM | 0.0 | 0.929 | 0.0 | 0.521 | 0.0 | 1.0 | 0.0 | 0.344 |
CAMK-II | 0.0 | 0.929 | 0.0 | 0.521 | 0.0 | 1.0 | 0.0 | 0.33 |
Proliferation | 0.0 | 0.956 | 0.0 | 0.141 | 0.0 | 1.0 | 0.0 | 0.148 |
Migration | 0.0 | 0.931 | 0.0 | 0.383 | 0.0 | 1.0 | 0.0 | 0.193 |
BAD | 0.0 | 0.192 | 0.0 | 0.994 | 0.0 | 0.0 | 0.0 | 0.892 |
BAX | 0.0 | 0.0 | 0.0 | 0.93 | 0.0 | 0.0 | 0.0 | 0.928 |
MOMP | 0.0 | 0.0 | 0.0 | 0.997 | 0.0 | 0.0 | 0.0 | 0.997 |
Cyto.C | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 0.0 | 1.0 |
Apoptosis | 0.0 | 0.0 | 0.0 | 1.0 | 0.0 | 0.0 | 0.0 | 1.0 |
Inhibitors | -- | -- | -- | -- | -- | -- | 1.0 | 0.0 |
Inositol Phosphate (IP) (Class A) | | |||||||||
No. | Molecule | Conformation | Positions | IC50 nM | Ref. | |||||
R1 | R2 | R3 | R4 | R5 | R6 | |||||
1A | DL-Ins(1,2,4,5)P4 | (R,S,R,S,S,S) | PO3−2 | PO3−2 | OH | PO3−2 | PO3−2 | OH | 26.5 | [48] |
2A | Ins(1,3,4,5)P4 | (R,S,S,S,R,S) | PO3−2 | OH | PO3−2 | PO3−2 | PO3−2 | OH | 2.9 | [47] |
3A | Ins(1,4,5,6)P4 | (R,S,S,R,R,S) | PO3−2 | OH | OH | PO3−2 | PO3−2 | PO3−2 | 430 | [47] |
4A | Ins(3,4,5,6)P4 | (S,R,R,S,R,R) | OH | OH | PO3−2 | PO3−2 | PO3−2 | PO3−2 | 620 | [47] |
5A | D-chiro-Ins(1,3,4,6)P4 | (R,S,R,S,S,R) | PO3−2 | OH | PO3−2 | PO3−2 | OH | PO3−2 | 172 | [48] |
6A | scyllo-Ins(1,2,4,5)P4 | (S,S,R,R,R,S) | PO3−2 | PO3−2 | OH | PO3−2 | PO3−2 | OH | 14 | [48] |
7A | DL-scyllo-Ins(1,2,4)P3 | (S,S,R,R,R,R) | PO3−2 | PO3−2 | OH | PO3−2 | OH | OH | 52 | [48] |
8A | Ins(1,4,5)P3 | (R,R,S,R,R,S) | PO3−2 | OH | OH | PO3−2 | PO3−2 | OH | 4.43 | [48] |
9A | Ins(1,5,6)P3 | (R,R,S,R,R,S) | PO3−2 | OH | OH | OH | PO3−2 | PO3−2 | 44 | [47] |
10A | Ins(3,4,5)P3 | (R,S,S,S,R,S) | OH | OH | PO3−2 | PO3−2 | PO3−2 | OH | 6.1 | [47] |
11A | Ins(4,5,6)P3 | (R,R,S,S,R,S) | OH | OH | OH | PO3−2 | PO3−2 | PO3−2 | 93,000 | [89] |
12A | Ins(4, 5)P2 | (R,R,S,R,S,S) | OH | OH | OH | PO3−2 | PO3−2 | OH | 20,000 | [89] |
Xestospongins (Xe) (Class B) | | |||||||||
No. | Molecule | Conformation | Positions | IC50 nM | clogP | Ref. | ||||
R1 | R2 | R5 | R8 | |||||||
C1 | C7 | C15 | C32 | |||||||
1B | Xestospongin_A | 1S,8S,10R,15S,22S,29R | --- | --- | --- | --- | 2535 | 8.01 | [90] | |
2B | 7-(OH)-XeA | 1S,7S,8R,10R,15S,22S,29R | --- | OH | --- | --- | 6400 | 6.70 | [91] | |
3B | Araguspongine B | 1R,8S,10R,15R,22S,29R | --- | -- | --- | --- | 648 | 8.01 | [90] | |
4B | Araguspongine C | 1R,8R,10S,15R,22R,29S | OH | --- | OH | --- | 6600 | 4.69 | [91] | |
5B | Xestospongin_B | 1S,8S,10R,15R,22S,29R,32R | --- | --- | OH | CH3 | 5000 | 7.29 | [92] | |
6B | De Methylated XeB | 1S,8S,10R,15R,22S,29R | --- | -- | OH | ---- | 5865 | 6.77 | [90] |
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Ismatullah, H.; Jabeen, I.; Saeed, M.T. Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer. Genes 2021, 12, 34. https://doi.org/10.3390/genes12010034
Ismatullah H, Jabeen I, Saeed MT. Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer. Genes. 2021; 12(1):34. https://doi.org/10.3390/genes12010034
Chicago/Turabian StyleIsmatullah, Humaira, Ishrat Jabeen, and Muhammad Tariq Saeed. 2021. "Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer" Genes 12, no. 1: 34. https://doi.org/10.3390/genes12010034