Saponins as a Potential PFN2 Inhibitor: In silico Approach

Abstract Colorectal cancer (CRC) disease has a high mortality rate and has recently involved human profilin II (Pfn2), an actin-binding protein, as a promoter of its invasiveness and progression. This work evaluated the binding affinity of oleanolic acid saponin over Pfn2 and its structural stability. QM and MM techniques were applied to perform geometrical optimization and calculation of the reactive sites from oleanolic acid, whereas molecular docking and MD simulations for protein-ligand interaction under physiological conditions. Oleanolic acid saponin showed a high binding affinity to the Pfn2 PLPbinding site. Analysis of the protein-ligand structure suggests saponin as a molecule with high potential for developing new drugs against Pfn2 in colorectal cancer cells.

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Evaluation of the Anticancer Properties of Geranyl Isovalerate, an Active Ingredient of Argyreia nervosa Extract in Colorectal Cancer Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2021.698375 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fayyaz Rasool ◽

Deepu Sharma ◽

P. Shanmukha Anand ◽

SKJ Magani ◽

Srinivasan Tantravahi

Keyword(s):

Colorectal Cancer ◽

Anticancer Activity ◽

Hct116 Cell ◽

Ethyl Acetate Fraction ◽

New Drugs ◽

Dependent Manner ◽

Secondary Complications ◽

Anticancer Properties ◽

Colorectal Cancer Cells ◽

Argyreia Nervosa

Chemotherapy is a general treatment procedure for cancer. The diversity in cancer incidence and the failure of therapy due to chemoresistance lead to increased cancer-related deaths. Therefore, new drugs with fewer secondary complications targeting diverse pathways are the need of the hour. Geranyl isovalerate (GIV), one of the active ingredients of ethyl acetate fraction of Argyreia nervosa is routinely used as a food flavoring agent. In this study, we found that GIV also exhibits anticancer activity when tested against the HCT116 cell line. It influenced the viability of the cells in a dose- and time-dependent manner. We examined whether GIV could induce oxidative stress and affect the mitochondrial membrane potential, thereby leading to apoptosis induction. Moreover, GIV could suppress the expression of antiapoptotic genes, such as BCl2 and PARP, and induce the expression of proapoptotic genes, such as Caspase 3 and 9. This is the first study demonstrating the anticancer activity of GIV and providing evidence for its mechanism of action. In conclusion, this study proposes GIV as a potential lead or supplementary molecule in treating and preventing colorectal cancer (CRC). Based on our findings, we conclude that GIV may be a viable lead or supplementary molecule for treating and preventing CRC.

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Structure-based Protein-ligand Interaction Fingerprints for Binding Affinity Prediction

Computational and Structural Biotechnology Journal ◽

10.1016/j.csbj.2021.11.018 ◽

2021 ◽

Author(s):

Debby D. Wang ◽

Moon-Tong Chan ◽

Hong Yan

Keyword(s):

Binding Affinity ◽

Ligand Interaction ◽

Binding Affinity Prediction ◽

Affinity Prediction ◽

Protein Ligand Interaction ◽

Interaction Fingerprints

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Behavior of Chemokine Receptor 6 (CXCR6) in Complex with CXCL16 Soluble form Chemokine by Molecular Dynamic Simulations: General Protein‒Ligand Interaction Model and 3D-QSAR Studies of Synthetic Antagonists

Life ◽

10.3390/life11040346 ◽

2021 ◽

Vol 11 (4) ◽

pp. 346

Author(s):

Giovanny Aguilera-Durán ◽

Antonio Romo-Mancillas

Keyword(s):

Molecular Dynamics ◽

3D Qsar ◽

Md Simulations ◽

Active State ◽

Activation Mechanism ◽

Soluble Form ◽

Ligand Interaction ◽

Protein Ligand Interaction ◽

Polar Interactions ◽

General Protein

The CXCR6‒CXCL16 axis is involved in several pathological processes, and its overexpression has been detected in different types of cancer, such as prostate, breast, ovary, and lung cancer, along with schwannomas, in which it promotes invasion and metastasis. Moreover, this axis is involved in atherosclerosis, type 1 diabetes, primary immune thrombocytopenia, vitiligo, and other autoimmune diseases, in which it is responsible for the infiltration of different immune system cells. The 3D structure of CXCR6 and CXCL16 has not been experimentally resolved; therefore, homology modeling and molecular dynamics simulations could be useful for the study of this signaling axis. In this work, a homology model of CXCR6 and a soluble form of CXCL16 (CXCR6‒CXCL16s) are reported to study the interactions between CXCR6 and CXCL16s through coarse-grained molecular dynamics (CG-MD) simulations. CG-MD simulations showed the two activation steps of CXCR6 through a decrease in the distance between the chemokine and the transmembrane region (TM) of CXCR6 and transmembrane rotational changes and polar interactions between transmembrane segments. The polar interactions between TM3, TM5, and TM6 are fundamental to functional conformation and the meta-active state of CXCR6. The interactions between D77-R280 and T243-TM7 could be related to the functional conformation of CXCR6; alternatively, the interaction between Q195-Q244 and N248 could be related to an inactive state due to the loss of this interaction, and an arginine cage broken in the presence of CXCL16s allows the meta-active state of CXCR6. A general protein‒ligand interaction supports the relevance of TM3‒TM5‒TM6 interactions, presenting three relevant pharmacophoric features: HAc (H-bond acceptor), HDn (H-bond donator), and Hph (hydrophobic), distributed around the space between extracellular loops (ECLs) and TMs. The HDn feature is close to TM3 and TM6; likewise, the HAc and Hph features are close to ECL1 and ECL2 and could block the rotation and interactions between TM3‒TM6 and the interactions of CXCL16s with the ECLs. Tridimensional quantitative structure-activity relationships (3D-QSAR) models show that the positive steric (VdW) and electrostatic fields coincide with the steric and positive electrostatic region of the exo-azabicyclo[3.3.1]nonane scaffold in the best pIC50 ligands. This substructure is close to the E274 residue and therefore relevant to the activity of CXCR6. These data could help with the design of new molecules that inhibit chemokine binding or antagonize the receptor based on the activation mechanism of CXCR6 and provoke a decrease in chemotaxis caused by the CXCR6‒CXCL16 axis.

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