Exploring binding mode assessment of novel kaempferol, resveratrol, and quercetin derivatives with PPAR-α as potent drug candidates against cancer.

Peroxisome proliferator-activated receptors (PPAR)-α, a ligand-activated transcription factor stands out to be a valuable protein target against cancer. Given that ligand binding is the crucial process for the activation of PPAR-α, fibrate class of synthetic compounds serves as potent agonist for the receptor. However, their serious side effects limit the long-term application in cancer. This emphasizes the dire need to identify new candidates that would exert desired activation by abrogating the adverse effects caused by synthetic agonists. Natural dietary products serve as an important source of drug discovery. Hence, the present study encompasses the investigation of the role of natural plant phenolic compounds: kaempferol, resveratrol, and quercetin and their 8708 derivatives by the means of computational pipeline comprising molecular docking and molecular dynamic (MD) simulation techniques. Docking calculations shortlisted potential candidates, namely 6-cinnamylchrysin (6-CC), resveratrol potassium-4-sulfate (RPS) and 6-[2-(3,4-Dihydroxyphenyl)-5-hydroxy-4-oxochromen-7-yl]oxyhexyl nitrate (DHOON), and derivatives of kaempferol, resveratrol, and quercetin, respectively. 6-CC, RPS, and DHOON manifested better affinities of - 32.83 kcal/mol (Ala333, Lys358, His440), - 27.22 kcal/mol (Tyr314, Met355), and - 30.18 kcal/mol (Ser280, Tyr314, Ala333), respectively, and were found to act as good stimulants for PPAR-α. Among these three compounds, 6-CC caused relatively least deviations and fluctuations analyzed through MD simulation which judiciously held responsible to attain most favorable interaction with PPAR-α. Followed by the binding free energy (ΔG) calculations using MM-GBSA confirmed the key role of 6-CC toward PPAR-α. The compound 6-CC also achieved high drug-likeness and pharmacokinetic properties. Thus, these findings stipulate new drug leads for PPAR-α receptor which abets a way to develop new anti-cancer drugs.

An in silico scientific basis for LL-37 as a therapeutic for Covid-19.

A multi-pronged approach with help in all forms possible is essential to completely overcome the Covid-19 pandemic. There is a requirement to research as many new and different types of approaches as possible to cater to the entire world population, complementing the vaccines with promising results. The need is also because SARS-CoV-2 has several unknown or variable facets which get revealed from time to time. In this work, in silico scientific findings are presented, which are indicative of the potential for the use of the LL-37 human anti-microbial peptide as a therapeutic against SARS-CoV-2. This indication is based on the high structural similarity of LL-37 to the N-terminal helix, with which the virus interacts, of the receptor for SARS-CoV-2, Angiotensin Converting Enzyme 2. Moreover, there is positive prediction of binding of LL-37 to the receptor-binding domain of SARS-CoV-2; this is the first study to have described this interaction. In silico data on the safety of LL-37 are also reported. As Vitamin D is known to upregulate the expression of LL-37, the vitamin is a candidate preventive molecule. This work provides the possible basis for an inverse correlation between Vitamin D levels in the body and the severity of or susceptibility to Covid-19, as widely reported in literature. With the scientific link put forth herein, Vitamin D could be used at an effective, medically prescribed, safe dose as a preventive. The information in this report would be valuable in bolstering the worldwide efforts to eliminate the pandemic as early as possible.

Novel B, C-ring truncated deguelin derivatives reveals as potential inhibitors of cyclin D1 and cyclin E using molecular docking and molecular dynamic simulation.

The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancers. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and cyclin E and thus suppressing its function. The C7a atomic position of deguelin structure contains a proton that generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To design deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivatives were investigated as cyclin D1 and cyclin E inhibitors. R-group-based enumeration was implemented in the deguelin scaffold using the R-group enumeration module of Schrödinger. Drug-Like filters like, REOS and PAINs series were applied to the enumerated compound library to remove compounds containing reactive functional groups. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP and XP protocol to obtain docking poses. Enrichment calculations were done using SchrÖdinger software, with 1000 decoy compounds (from DUD.E database) and 60 compounds (XP best poses) along with deguelin, to validate the docking protocol. The receiver operating characteristic (ROC) curve indicates R2 = 0.94 for cyclin D1 and R2 = 0.79 for cyclin E, suggesting that the docking protocol is valid. Besides, we explored molecular dynamics simulation to probe the binding stability of deguelin and its derivatives within the binding cavity of cyclin D1 and cyclin E structures which are associated with the cyclin D1 and cyclin E inhibitory mechanism.

Exploring the anticancer potential of fluoro flavone analogues: insights from molecular docking and dynamics studies with Aurora Kinase B.

Aurora Kinase B belongs to the serine kinase family. It plays an essential role in cell division and participates in mitosis and chromatid segregation. Overexpression, polymorphism, and splicing variants in the protein lead to tumorigenesis, leading to cancer. Flavones belong to the class of flavonoids and are derived from plants and show anti-cancer activities. Fluoro flavones and their analogs are taken from the PubChem database, resulting in 3882 compounds which is 90% similar to the fluoro flavones. Lipinski's rule of five, REOS and PAINS drug-like filters were applied which resulted 2448 compounds. These compounds are docked with Aurora Kinase B using SP and XP modules of Glide software. The best binding scores for SP docking were - 9.153 kcal/mol for the compound with CID: 44298667, and XP docking was - 10.287 kcal/mol with CID: 101664315. Enrichment calculations were done using Aurora Kinase B's decoys to validate the docking result. The resulting R2 = 0.96 from enrichment calculations suggests that the docking protocol is valid. The SP and XP docking lead compounds and the Fluoro flavone were subjected to 100 ns MD simulation to probe the protein-ligand complex stability. Also, the binding free energies between the Aurora kinase B and lead compounds were computed by Prime MM/GBSA module. The result suggests that the lead compounds bind more strongly with Aurora Kinase B than the Fluoro flavone. These lead compounds can be further evaluated in vitro and in vivo and can be used as future novel drugs for the curation of cancer.

Elevated N1-Acetylspermidine Levels in Doxorubicin-treated MCF-7 Cancer Cells: Histone Deacetylase 10 Inhibition with an N1-Acetylspermidine Mimetic.

Cancer drug resistance is associated with metabolic adaptation. Cancer cells have been shown to implicate acetylated polyamines in adaptations during cell death. However, exploring the mimetic of acetylated polyamines as a potential anticancer drug is lacking. We performed intracellular metabolite profiling of human breast cancer MCF-7 cells treated with doxorubicin (DOX), a well known anticancer drug. A novel and in-house vertical tube gel electrophoresis assisted procedure followed by LC-HRMS analysis was employed to detect acetylated polyamines such as N1-acetylspermidine. We designed a mimetic N1-acetylspermidine (MINAS) which is a known substrate of histone deacetylase 10 (HDAC10). Molecular docking and molecular dynamics (MDs) simulations were used to evaluate the inhibitory potential of MINAS against HDAC10. The inhibitory potential and the ADMET profile of MINAS were compared to a known HDAC10 inhibitor Tubastatin A. N1-acetylspermidine, an acetylated form of polyamine, was detected intracellularly in MCF-7 cells treated with DOX over DMSO-treated MCF-7 cells. We designed and curated MINAS (PubChem CID 162679241). Molecular docking and MD simulations suggested the strong and comparable inhibitory potential of MINAS (-8.2 kcal/mol) to Tubastatin A (-8.4 kcal/mol). MINAS and Tubastatin A share similar binding sites on HDAC10, including Ser138, Ser140, Tyr183, and Cys184. Additionally, MINAS has a better ADMET profile compared to Tubastatin A, with a high MRTD value and lower toxicity. In conclusion, the data show that N1-acetylspermidine levels rise during DOX-induced breast cancer cell death. Additionally, MINAS, an N1-acetylspermidine mimetic compound, could be investigated as a potential anticancer drug when combined with chemotherapy like DOX.

Exploring the role of TLK2 mutation in tropical calcific pancreatitis: an in silico and molecular dynamics simulation study.

Tropical calcific pancreatitis (TCP) is a juvenile form of non-alcoholic chronic pancreatitis seen exclusively in tropical countries. The disease poses a high risk of complications, including pancreatic diabetes and cancer, leading to significant mortality due to poor diagnosis and ineffective treatments. This study employed whole exome sequencing (WES) of 5 TCP patient samples to identify genetic variants associated with TCP. Advanced computational techniques were used to gain atomic-level insights into disease progression, including microsecond-scale long MD simulations and essential dynamics. In silico virtual screening was performed to identify potential therapeutic compounds targeting the mutant protein using the Asinex and DrugBank compound library. WES analysis predicted several single nucleotide variants (SNVs) associated with TCP, including a novel missense variant (c.T1802A or p.V601E) in the TLK2 gene. Computational analysis revealed that the p.V601E mutation significantly affected the structure of the TLK2 kinase domain and its conformational dynamics, altering the interaction profile between ATP and the binding pocket. These changes could impact TLK2's kinase activity and functions, potentially correlating with TCP progression. Promising lead compounds that selectively bind to the TLK2 mutant protein were identified, offering potential for therapeutic interventions in TCP. These findings hold great potential for future research.Communicated by Ramaswamy H. Sarma.

Intracellular Ellagic Acid Derived from Goat Urine DMSO Fraction (GUDF) Predicted as an Inhibitor of c-Raf Kinase.

BACKGROUND: Dietary chemicals and their gut-metabolized products are explored for their anti-proliferative and pro-cell death effects. Dietary and metabolized chemicals are different from ruminants such as goats over humans. METHODS: Loss of cell viability and induction of death due to goat urine DMSO fraction (GUDF) derived chemicals were assessed by routine in vitro assays upon MCF-7 breast cancer cells. Intracellular metabolite profiling of MCF-7 cells treated with goat urine DMSO fraction (GUDF) was performed using an in-house designed vertical tube gel electrophoresis (VTGE) assisted methodology, followed by LC-HRMS. Next, identified intracellular dietary chemicals such as ellagic acid were evaluated for their inhibitory effects against transducers of the c-Raf signaling pathway employing molecular docking and molecular dynamics (MD) simulation. RESULTS: GUDF treatment upon MCF-7 cells displayed significant loss of cell viability and induction of cell death. A set of dietary and metabolized chemicals in the intracellular compartment of MCF-7 cells, such as ellagic acid, 2-hydroxymyristic acid, artelinic acid, 10-amino-decanoic acid, nervonic acid, 2,4-dimethyl-2-eicosenoic acid, 2,3,4'- Trihydroxy,4-Methoxybenzophenone and 9-amino-nonanoic acid were identified. Among intracellular dietary chemicals, ellagic acid displayed a strong inhibitory affinity (-8.7 kcal/mol) against c-Raf kinase. The inhibitory potential of ellagic acid was found to be significantly comparable with a known c-Raf kinase inhibitor sorafenib with overlapping inhibitory site residues (ARG450, GLU425, TRP423, VA403). CONCLUSION: Intracellular dietary-derived chemicals such as ellagic acid are suggested for the induction of cell death in MCF-7 cells. Ellagic acid is predicted as an inhibitor of c-Raf kinase and could be explored as an anti-cancer drug.

Screening of potential phytomolecules against MurG as drug target in nosocomial pathogen Pseudomonas aeruginosa: perceptions from computational campaign.

The nosocomial infection outbreak caused by Pseudomonas aeruginosa remains a public health concern. Multi-drug resistant (MDR) strains of P. aeruginosa are rapidly spreading leading to a huge mortality rate because of the unavailability of promising antimicrobials. MurG glycotransferase [UDP-N-acetylglucosamine-N-acetylmuramyl (pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase] is located at the plasma membrane and plays a key role in murein (peptidoglycan) biosynthesis in bacteria. Since MurG is required for bacterial cell wall synthesis and is non-homologous to Homo sapiens; it can be a potential target for the antagonist to treat P. aeruginosa infection. The discovery of high-resolution crystal structure of P. aeruginosa MurG offers an opportunity for the computational identification of its prospective inhibitors. Therefore, in the present study, the crystal structure of MurG (PDB ID: 3S2U) from P. aeruginosa was selected, and computational docking analyses were performed to search for functional inhibitors of MurG. IMPPAT (Indian medicinal plants, phytochemicals and therapeutic) phytomolecule database was screened by computational methods with MurG catalytic site. Docking results identified Theobromine (-8.881 kcal/mol), demethoxycurcumin (-8.850 kcal/mol), 2-alpha-hydroxycostic acid (-8.791 kcal/mol), aurantiamide (-8.779 kcal/mol) and petasiphenol (-8.685 kcal/mol) as a potential inhibitor of the MurG activity. Further, theobromine and demethoxycurcumin were subjected to MDS (molecular dynamics simulation) and free energy (MM/GBSA) analysis to comprehend the physiological state and structural stability of MurG-phytomolecules complexes. The outcomes suggested that these two phytomolecules could act as most favorable natural hit compounds for impeding the enzymatic action of MurG in P. aeruginosa, and thus it needs further validation by both in vitro and in vivo analysis. HIGHLIGHTSThe top phytomolecules such as theobromine, demethoxycurcumin, 2-alpha-hydroxycostic acid, aurantiamide and petasiphenol displayed promising binding with MurG catalytic domain.MurG complexed with theobromine and demethoxycurcumin showed the best interaction and stable by MD simulation at 100 ns.The outcome of MurG binding phytomolecules has expanded the possibility of hit phytomolecules validation.Communicated by Ramaswamy H. Sarma.

Molecular Docking and Simulation Studies of Flavanone and its Derived Compounds on PI3K-AKT Pathway Targeting against Cancer.

BACKGROUND: Flavanone compounds and their related derivatives are reported in controlling cell cycle, angiogenesis, and metastasis. Phosphoinositide 3-kinases is a major drug target. METHODS: Crystalize structure of Phosphoinositide 3-kinases-Akt complex obtained from Protein Data Bank (PDBID: 3CQW) was selected as receptor protein and the binding site has been identified with PDBSum Database. Flavanone and its derivatives were retrieved using freely available existing drug databases like Drug Bank, Zinc, and PubChem. New derivatives were modified by altering the flavanone at Beta ring position. This modification would help in maintaining stable structural conformation and retaining better anticancer activity. Retrieved Flavanone derivatives from the drug database were docked against 3CQW Protein with the advanced docking tool FlexX. MD simulations of the best molecule were performed with the Desmond package by calculating nonbonding interactions such as electrostatic interaction and hydrogen bond stable and favorable conformations were calculated. RESULTS: These interaction studies would help identify new potential drug candidates with the help of computer-aided drug designing techniques. CONCLUSION: Natural chemicals have received a lot of attention because of their vast range of applications in human health and disease prevention without creating any negative side effects. Molecular docking is an essential approach for drug development since it allows for effective screening of potential therapeutics in a short time. We hypothesized in this paper that natural flavanone and its derivatives may be effective as Akt-1 inhibitors.

Docking and simulation studies on cyclin D/CDK4 complex for targeting cell cycle arrest in cancer using flavanone and its congener.

Flavanone compounds are naturally occurring phytochemicals present in most of citrus fruits reported to be a potential anticancer moiety as it majorly participates in the inhibition of the cell cycle, apoptosis, and angiogenesis. Because of poor bioavailability, natural flavanones were not used as therapeutic targets so flavanone congeners were prepared by modifying at B-functional group using compound libraries such as PubChem Database. Cyclin-dependent kinase is primarily activating the cell cycle and potentiating the M phase, in order to control the cell cycle in cancer cyclin-dependent pathway was targeted and potential cyclin D/CDK4 receptor protein was retrieved from Protein Data Bank (PDBID:2W9Z). The binding site was determined using FlexX docking. Flavanone and its congeners were docked against the 2W9Z receptor protein with the docking software FlexX. For validation of docking results, molecular dynamics simulations of the best-fitting molecule were carried out using Desmond Package. Noncovalent interactions like hydrogen bonds, electrostatic interaction, and Van der walls potentials for stable conformations were calculated. Thus, upon docking and molecular dynamics studies, we discovered the potential flavanone derivatives such as Flavanone 20, Flavanone 25, and Flavanone 29, will become a potential drug target in controlling cell cycle arrest and may become a futuristic candidate in targeting cancer.