Campesterol and dithymoquinone as a potent inhibitors of SARS cov-2 main proteases-promising drug candidates for targeting its novel variants.

The sudden outbreak of the COVID-19 pandemic has currently taken approximately 2.4 million lives, with no specific medication and fast-tracked tested vaccines for prevention. These vaccines have their own adverse effects, which have severely affected the global healthcare system. The discovery of the main protease structure of coronavirus (Mpro/Clpro) has resulted in the identification of compounds having antiviral potential, especially from the herbal system. In this study, the computer-associated drug design tools were utilised to analyze the reported phytoconstituents of Nigella sativa for their antiviral activity against the main protease. Fifty-eight compounds were subjected to pharmacological parameter analysis to determine their lead likeness in comparison to the standard drugs (chloroquine and nirmatrelvir) used in the treatment of SARS-CoV-2. Nearly 31 compounds were docked against five different SARS-CoV-2 main proteases, and all compounds showed better binding affinity and inhibition constant against the proteases. However, dithymoquinone and campesterol displayed the best binding scores and hence were further subjected to dynamics and MMPBSA study for 100 ns. The stability analysis shows that dithymoquinone and campesterol show less variation in fluctuation in residues compared to standard complexes. Moreover, dithymoquinone exhibited higher binding affinity and favorable interaction followed by campesterol as compared to the standard drug. The in silico computational analysis provides a promising hit for regulating the main proteases activity.Communicated by Ramaswamy H. Sarma.

HDAC inhibition by Nigella sativa L. sprouts extract in hepatocellular carcinoma: an approach to study anti-cancer potential.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

Molecular docking and molecular dynamics simulation analysis of bioactive compounds of Cichorium intybus L. seed against hepatocellular carcinoma.

In this article, bioactive compounds present in Cichorium intybus L. seeds were collected from literature review and analyzed for probable remedy for hepatocellular carcinoma. Cichorium intybus L. is a traditional plant used all over the world mainly in hepatic disorders and renal diseases. This therapeutic plant has many bioactive compounds like chicoric acid, chlorogenic acid, sesquiterpne lactones, stigmasterols etc are found in seeds. Here, the target protein p53 (PDB ID: 2OCJ) which is involved in many cancerous pathways, is chosen. The preADMET study filtered out some compounds which were then subjected to molecular docking studies by Autodock tool 4.2. Afterwards, two best compounds (Esculetin and Isochlorogenic acid) were screened out on the basis of binding energy as compared to the standard compound (Doxorubicin). All these complexes were then analyzed for stability by molecular dynamics using online GROMACS tool. In the comparative simulation study, the compound Esculetin shows a stable interaction with the p53 over the 100 ns trajectory. Hepatocellular carcinoma accounts for high mortality of cancer related death worldwide. These findings suggest that these compound can be used to treat the hepatocellular carcinoma.Communicated by Ramaswamy H. Sarma.

Computational modeling of cyanobacterial phytoconstituents against toll-like receptors of skin cancer.

Melanoma is an extremely dangerous disease. The diagnosis and treatment of it may be difficult because of its diversity and complexity. More than 90% of the marine biomass (microflora and microalgae) constitutes the natural biodiversity reserves. TLR-related research developments indicate possible cancer therapeutic possibilities. In addition to its significant function in innate immunity, TLR activation is connected to the start of pyroptosis, apoptosis, or autophagy in malignance cells. For these reasons, TLR agonists are appealing candidates for the production of cancer medications. From the web databases, the ternary structures of the receptors (TLR3 and TLR4) and ligands are extracted. Sixty-nine compounds were subjected to a drug likeness filter, but only twenty-two were screened further for evaluating ADMET criteria, in which only seven compounds satisfied the pharmacological properties. These compounds are further analyzed for docking parameters against TLRs (TLR3 and TLR4) and molecular simulation investigation of the best cluster to evaluate the complex stability. Molecular docking methodology discovered that Scytonmein has a significant binding potential energy of -5.21 and -7.92 kcal/mol against TLR3 and TLR4, respectively, in comparison to the redock co-crystal structure (-3.98 and -4.30 kcal/mol, respectively). The simulation analysis demonstrates the significant stability of the Scytonemin and TLR4 complexes in terms of average RMSD and RMSF compared to the redock complex, while criteria like solvent-accessible surface area (SASA), gyration (Rg) and hydrogen bonding have further supported the significant interaction and stability of the conformations.Communicated by Ramaswamy H. Sarma.

Computational identification of bioactive compounds from Cydonia oblonga Mill. against hepatocellular carcinoma by targeting pTEN and HBx-interacting protein.

Phytochemicals derived from Cydonia oblonga have been investigated for their anti-oxidant and anti-cancer activities in various cancer cell lines. The reported bioactive compounds are evaluated in silico to develop a novel antagonist against pTEN (phosphatase and tensin homolog) and HBx (hepatitis B X-interacting protein) to target hepatocellular carcinoma. Lower expression of pTEN or higher expression of HBx represents the progression of hepatocellular carcinoma. This research is intended to identify the best candidate who interacts with our target proteins (pTEN and HBx) from the quince seeds by using computational methodologies. The ternary structures of the proteins and phytochemicals are retrieved from the online databases (RCSB and PubChem). The drug likeness analysis of the reported seventeen compounds was done, but only five follow the selection criteria. ADMET profiling of these five compounds was done, followed by docking analysis and molecular dynamics study of the best complexes to determine the stability of the complexes. A docking study revealed that caffeoylquinic acids (CQA) derivatives have the significant inhibitory potential of 3-O-caffeoylquinic acid (3CQA) and 5-O-caffeoylquinic acid (5CQA) with binding affinity of - 7.53 and - 7.49 against pTEN and - 5.94 and - 6.01 against HBx in comparison to the doxorubicin. The average root mean square deviation and root mean square fluctuation values for protein-ligand complexes were found quite stable compared to the standard, while parameters like gyration and SASA (solvent-accessible surface area) supported the complexes significant binding and stability. The results obtained from the evaluation show that 3CQA and 5CQA have the best stability, especially with the pTEN protein target. Hence, these compounds have to be considered for detailed experimental studies to understand their biological function against hepato-carcinoma.