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Correlation between Molecular Docking and the Stabilizing Interaction of HOMO-LUMO: Spirostans in CHK1 and CHK2, an
Antonio Rosales-López1, Guiee N López-Castillo1,2, Jesús Sandoval-Ramírez1,2
1Laboratorio de Elucidación y Síntesis en Química Orgánica, Instituto de Ciencias, BUAP, Puebla 72570, Mexico.
Abstract:
Checkpoint kinases 1 and 2 (CHK1 and CHK2) are enzymes that are involved in the control of DNA damage. At the present time, these enzymes are some of the most important targets in the fight against cancer since their inhibition produces cytotoxic effects in carcinogenic cells. This paper proposes the use of spirostans (Sp), natural compounds, as possible inhibitors of the enzymes CHK1 and CHK2 from an in silico analysis of a database of 155 molecules (S5). Bioinformatics studies of molecular docking were able to discriminate between 13 possible CHK1 inhibitors, 13 CHK2 inhibitors and 1 dual inhibitor for both enzymes. The administration, distribution, metabolism, excretion and toxicity (ADMETx) studies allowed a prediction of the distribution and metabolism of the potential inhibitors in the body, as well as determining the excretion routes and the appropriate administration route. The best inhibition candidates were discriminated by comparing the enzyme-substrate interactions from 2D diagrams and molecular docking. Specific inhibition candidates were obtained, in addition to studying the dual inhibitor candidate and observing their stability in dynamic molecular studies. In addition, Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) interactions were analyzed to study the stability of interactions between the selected enzymes and spirostans resulting in the predominant gaps from HOMOCHKs to LUMOSp (Highest Occupied Molecular Orbital of CHKs-Lowest Unoccupied Molecular Orbital of spirostan). In brief, this study presents the selection inhibitors of CHK1 and CHK2 as a potential treatment for cancer using a combination of molecular docking and dynamics, ADMETx predictons, and HOMO-LUMO calculation for selection.
Insights
Spirostans, natural compounds, show potential as inhibitors for checkpoint kinases 1 and 2 (CHK1/CHK2), crucial targets in cancer therapy. In silico analysis identified specific spirostan candidates for further development as anti-cancer agents.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- Checkpoint kinases 1 and 2 (CHK1 and CHK2) are critical regulators of DNA damage response.
- Inhibition of CHK1 and CHK2 shows promise for cancer treatment due to cytotoxic effects on cancer cells.
- Natural compounds are being explored as novel therapeutic agents.
Purpose of the Study:
- To identify potential spirostan inhibitors of CHK1 and CHK2 using in silico methods.
- To evaluate the drug-likeness and stability of identified spirostan candidates.
- To explore the potential of spirostans as a novel class of anti-cancer drugs targeting DNA damage pathways.
Main Methods:
- In silico molecular docking of a database of 155 spirostan molecules against CHK1 and CHK2.
- ADMETx (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions for potential inhibitors.
- Molecular dynamics simulations and HOMO-LUMO analysis to assess binding stability and interactions.
Main Results:
- Identification of 13 potential CHK1 inhibitors, 13 CHK2 inhibitors, and 1 dual CHK1/CHK2 inhibitor from the spirostan database.
- Prediction of ADMETx properties, guiding selection of suitable candidates and administration routes.
- Confirmation of binding stability and specific interactions through molecular dynamics and HOMO-LUMO analysis.
Conclusions:
- Spirostans represent a promising class of natural compounds for developing CHK1 and CHK2 inhibitors.
- In silico approaches, including molecular docking, dynamics, and ADMETx, are effective for identifying potential anti-cancer drug candidates.
- Further experimental validation is warranted to confirm the therapeutic potential of selected spirostan inhibitors against cancer.
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