Eco-friendly porous composite of octaphenyl polyhedral oligomeric silsesquioxane and HKUST-1 with hydrophobic-oleophilic properties towards sorption of oils and organic solvents.

The degradation of water bodies caused by organic pollutants from industrial wastewater discharge has made it necessary to develop new functional materials like hydrophobic-oleophilic materials that can efficiently remediate water. It is factual that many of the synthetic methods for creating hydrophobic-oleophilic materials involve the use of toxic or harmful reactants, such as fluorine or sulfur compounds. However, these methods often have significant drawbacks, including being hazardous to the environment, expensive, and complex to utilize. Therefore, there is an urgent need to develop a hydrophobic/oleophilic material that is non-toxic and eco-friendly in order to overcome the existing drawbacks. In this regard, we have proposed a modest and eco-friendly approach for constructing a hydrophobic-oleophilic Ph-POSS@HKUST-1 composite material by solution-assisted self-assembly for the conversion of hydrophilic HKUST-1 into hydrophobic HKUST-1 for separation applications. The incorporation of fluorine-free, low surface energy and hydrophobic POSS into HKUST-1 increased the hydrophobicity and oleophilicity of the system. The synthesized Ph-POSS@HKUST-1 composite material has been thoroughly characterized through FT-IR, PXRD, HR-SEM, BET, and thermogravimetric analysis. It has been observed that the material exhibits a contact angle of 137 ± 4° and shows high selectivity and absorption capacity towards organic solvents and oils from water mixtures. Concurrently, the Ph-POSS@HKUST-1@PDA@sponge has been effectively utilized for the separation of solvents and oils and it has shown more than 95% separation efficiency for up to 15 cycles. It is interesting to note that Ph-POSS@HKUST-1 and the Ph-POSS@HKUST-1@PDA@sponge have outstanding stability in abrasive chemical environments which is due to the presence of a mechanically and chemically stable inorganic-organic hybrid POSS nanocage. In addition, ab initio and DFT calculations elicit that the Ph-POSS@HKUST-1 composite is stabilized through π⋯π stacking instead of the C-H⋯π mode of interaction at the HKUST-1⋯Ph-POSS interface. Further electron density features confirm the interfacial interaction at the interface. Our latest research has led us to propose an eco-friendly and non-toxic hybrid composite material for efficiently tackling the issue of organic solvent and oil pollution in water mixtures.

Evaluation of the efficacy of marine natural products against PARP-1/2 proteins in high-grade serous ovarian cancer: insights into MD and SMD simulations.

High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC.Communicated by Ramaswamy H. Sarma.

Dual Anti-Inflammatory and Anticancer Activity of Novel 1,5-Diaryl Pyrazole Derivatives: Molecular Modeling, Synthesis, In Vitro Activity, and Dynamics Study.

A series of novel 1,5-diaryl pyrazole derivatives targeting the COX enzyme were designed by combined ligand and structure-based approach. The designed molecules were then further subjected to ADMET and molecular docking studies. Out of 34 designed compounds, the top-10 molecules from the computation studies were synthesized, characterized, and evaluated for COX-2 inhibition and anti-cancer activity. Initially, the target compounds were screened for the protein denaturation assay. The results of the top-five molecules T2, T3, T5, T6, and T9 were further subjected to in vitro COX-2 enzymatic assay and anti-cancer activity. As far as COX-2 inhibitory activity is considered, two compounds, T3 and T5, exhibited the half maximum inhibitory concentration (IC50) at 0.781 µM and 0.781 µM respectively. Further, the two compounds T3 and T5, when evaluated for COX-1 inhibition, exhibited excellent inhibitory activity with T3 IC50 of 4.655µM and T5 with IC50 of 5.596 µM. The compound T5 showed more significant human COX-2 inhibition, with a selectivity index of 7.16, when compared with T3, which had a selectivity index of 5.96. Further, in vitro anti-cancer activity was screened against two cancer cell lines in which compounds T2 and T3 were active against A549 cell lines and T6 was active against the HepG2 cell line. Stronger binding energy was found by comparing MM-PBSA simulations with molecular docking, which suggests that compounds T3 and T5 have a better possibility of being effective compounds, in which T5 showed higher binding affinity. The results suggest that these compounds have the potential to develop effective COX-2 inhibitors as anti-cancer agents.

Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a computational study.

Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (-25.64 and -23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (-10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.

Formation of Eigen or Zundel Features at Protonated Water Cluster-Aromatic Interfaces.

Interfacial interactions of protonated water clusters adsorbed at aromatic surfaces play an important role in biology, and in atmospheric, chemical and materials sciences. Here, we investigate the interaction of protonated water clusters ((H+ H2 O)n (where n=1-3)) with benzene (Bz), coronene (Cor) and dodecabenzocoronene (Dbc)). To study the structure, stability and spectral features of these complexes, computations are done using DFT-PBE0(+D3) and SAPT0 methods. These interactions are probed by AIM electron density topography and non-covalent interactions index (NCI) analyses. We suggest that the excess proton plays a crucial role in the stability of these model interfaces through strong inductive effects and the formation of Eigen or Zundel features. Also, computations reveal that the extension of the π-aromatic system and the increase of the number of water molecules in the H-bounded water network led to a strengthening of the interactions between the corresponding aromatic compound and protonated water molecules, except when a Zundel ion is formed. The present findings may serve to understand in-depth the role of proton localized at aqueous medium interacting with large aromatic surfaces such as graphene interacting with acidic liquid water. Besides, we give the IR and UV-Vis spectra of these complexes, which may help for their identification in laboratory.

Discovery of novel HDAC8 inhibitors from natural compounds by in silico high throughput screening.

A class I histone deacetylase HDAC8 is associated with several diseases, including cancer, intellectual impairment and parasite infection. Most of the HDAC inhibitors that have so far been found to inhibit HDAC8 limit their efficacy in the clinic by producing toxicities. It is therefore very desirable to develop specific HDAC8 inhibitors. The emergence of HDAC inhibitors derived from natural sources has become quite popular. In recent decades, it has been shown that naturally occurring HDAC inhibitors have strong anticancer properties. A total of 0.2 million natural compounds were screened against HDAC8 from the Universal Natural Product Database (UNPD). Molecular docking was performed for these natural compounds and the top six hits were obtained. In addition, molecular dynamics (MD) simulations were used to evaluate the structural stability and binding affinity of the inhibitors, which showed that the protein-ligand complexes remained stable throughout the 100 ns simulation. MM-PBSA method demonstrated that the selected compounds have high affinity towards HDAC8. We infer from our findings that Hit-1 (-29.35 kcal mol-1), Hit-2 (-29.15 kcal mol-1) and Hit-6 (-30.28 kcal mol-1) have better binding affinity and adhesion to ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics against HDAC8. To compare our discussions and result in an effective way. We performed molecular docking, MD and MM-PBSA analysis for the FDA-approved drug romidepsin. The above results show that our hits show better binding affinity than the compound romidepsin (-12.03 ± 4.66 kcal mol-1). The important hotspot residues Asp29, Ile34, Trp141, Phe152, Asp267, Met274 and Tyr306 have significantly contributed to the protein-ligand interaction. These findings suggest that in vitro testing and additional optimization may lead to the development of HDAC8 inhibitors.Communicated by Ramaswamy H. Sarma.

Compounds from diverse natural origin against triple-negative breast cancer: A comprehensive review.

Triple-negative breast cancer (TNBC) is caused due to the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor 2 (HER2) expression. Triple-negative breast cancer is the most aggressive heterogeneous disease that is capable of producing different clones and mutations. Tumorigenesis in TNBC is caused due to the mutation or overexpression of tumor suppressor genes. It is also associated with mutations in the BRCA gene which is linked to hereditary breast cancer. In addition, PARP proteins and checkpoint proteins also play a crucial function in causing TNBC. Many cell signaling pathways are dysregulated in TNBC. Even though chemotherapy and immunotherapy are good options for TNBC treatment, the response rates are still low in general. Many phytochemicals that are derived from natural compounds have shown very good inhibitions for TNBC. Natural compounds have the great advantage of being less toxic, having lesser side effects, and being easily available. The secondary metabolites such as alkaloids, terpenoids, steroids, and flavonoids in natural products make them promising inhibitors of TNBC. Their compositions also offer vital insights into inhibitory action, which could lead to new cancer-fighting strategies. This review can help in understanding how naturally occurring substances and medicinal herbs decrease specific tumors and pave the way for the development of novel and extremely efficient antitumor therapies.