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.

In-silico screening of phytomolecules against multiple targets for wound management.

Chronic wound healing, especially in burns, is a major medical challenge with limited treatments. This study employs computational tools to identify phytomolecules that target multiple pathways involved in wound healing. By utilizing shape analysis, molecular docking, and binding energy calculations, potential compounds are pinpointed,to address the growing problem of chronic wounds. Initially, a set of phytomolecules from the ZINC database of natural molecules was screened to find compounds with shapes similar to well-known wound healing phytomolecules like curcumin, chromogenic acid, gallic acid, and quercetin. The most promising phytomolecules identified through shape similarity were further studied through molecular docking studies on several key targets involved in wound healing, including TNF-α, FGF, and TGF-ß. Among the tested phytomolecules, a ligand known as Fluorophenyl(5-(5-chloro-1-(2-fluorophenyl)-2-oxopentyl)-4,5,6,7-tetrahydrothieno[3,2c]pyridine-2-yl acetate) exhibited a strong affinity with favourable binding interactions for TNF-α ( - 7.1 kcal/mole), FGF (-6.9 kcal/mole), and TGF-ß (-5.1 kcal/mole). Another compound, 2,4 methoxybenzylidene-(-3)-oxo-2,3-dihydro-1-benzofuran-6-yl-4-methoxybenzoate, demonstrated a strong affinity with low binding energy for TNF-α ( - 6.8 kcal/mole) and FGF ( - 7.0 kcal/mole) targets. Isosakuranetin and Ermanin displayed moderate affinity for both TNF-α and FGF, with the highest affinity observed for the TGF-ß target. These findings suggest that these identified phytomolecules hold promise as potential lead compounds for further structural modifications, with the goal of designing new molecules that can target multiple pathways involved in the wound healing process.

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.

Secretion of Sphinganine by Drug-Induced Cancer Cells and Modified Mimetic Sphinganine (MMS) as c-Src Kinase Inhibitor.

BACKGROUND: Cancer cells exhibit selective metabolic reprogramming to promote proliferation, invasiveness, and metastasis. Sphingolipids such as sphingosine and sphinganine have been reported to modulate cell death processes in cancer cells. However, the potential of extracellular sphinganine and its mimetic compounds as inducers of cancer cell death has not been thoroughly investigated. METHODS: We obtained extracellular conditioned medium from HCT-116 cells treated with the previously reported anticancer composition, goat urine DMSO fraction (GUDF). The extracellular metabolites were purified using a novel and in-house developed vertical tube gel electrophoresis (VTGE) technique and identified through LC-HRMS. Extracellular metabolites such as sphinganine, sphingosine, C16 sphinganine, and phytosphingosine were screened for their inhibitory role against intracellular kinases using molecular docking. Molecular dynamics (MD) simulations were performed to study the inhibitory potential of a novel designed modified mimetic sphinganine (MMS) (Pubchem CID: 162625115) upon c-Src kinase. Furthermore, inhibitory potential and ADME profile of MMS was compared with luteolin, a known c-Src kinase inhibitor. RESULTS: Data showed accumulation of sphinganine and other sphingolipids such as C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0) in the extracellular compartment of GUDF-treated HCT-116 cells. Molecular docking projected c-Src kinase as an inhibitory target of sphinganine. MD simulations projected MMS with strong (-7.1 kcal/mol) and specific (MET341, ASP404) binding to the inhibitory pocket of c-Src kinase. The projected MMS showed comparable inhibitory role and acceptable ADME profile over known inhibitors. CONCLUSION: In summary, our findings highlight the significance of extracellular sphinganine and other sphingolipids, including C16 sphinganine, phytosphingosine, and ceramide (d18:1/14:0), in the context of drug-induced cell death in HCT-116 cancer cells. Furthermore, we demonstrated the importance of extracellular sphinganine and its modified mimetic sphinganine (MMS) as a potential inhibitor of c-Src kinase. These findings suggest that MMS holds promise for future applications in targeted and combinatorial anticancer therapy.

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.

Identification and Screening of Novel Anti-Cancer Compounds for Aurora Kinase-A from Chemical Database.

Aurora kinase is a group of enzymes that belongs to a serine-threonine family and plays a critical role in cellular division. Aurora Kinase A is overexpressed and distributed beyond the nucleus and is involved in tumorigenesis. Flavones are a class of flavonoids that are present in plants that show anticancer activity. Similar compounds of 2'Fluoroflavones are retrieved from the PubChem database. Then drug-like filters viz. REOS and PAINS were applied to remove toxic compounds using Canvas software, resulting in 3882 compounds being subjected to Glide docking with Aurora kinase A. The lead compounds were selected on the merit of hydrogen bonding, salt bridge, as well as pi-pi interactions, 4-(6-Fluoro-4-oxychromen-2yl) benzoic acid, has been found one of the best molecules from docking studies. The binding mode of the lead compound with AURKA reveals that the amino acid residues viz, Lys162, Ala213, and His280 are more important for binding with the binding affinity of -11.760 kcal/mol. The molecular dynamics simulations of 100 ns were done, which shows the mean RMSD value of 1.77 Å for all 3 complexes of the protein and Fluoroflavone and its analogs. This shows that Fluoroflavone and its 2 best analogs are tightly attached to the active sites and thus have conformational stability. Our finding suggests that 4-(6-fluoro-4-oxochromen-2-yl)benzoic acid and 4-(4-Oxochromen-2-yl)benzoate can be further used in vitro and in vivo experiments and can probably serve as a novel drug for cancer treatment.

In silico discovery of potent inhibitors against monkeypox's major structural proteins.

Monkeypox virus (MPXV) outbreak in non-endemic countries is a worldwide public health emergency. An enveloped double-stranded DNA virus belongs to the genus Orth poxvirus. A viral zoonotic infection known as monkeypox has been a serious risk to public health, especially in Africa. However, it has recently spread to other continents, so it might soon become a worldwide problem. There is an increased risk of transmission of the virus because there is a lack of effective treatment that cures the disease. To stop the multi-country outbreak from spreading, it is important to discover effective medications urgently. The objective of the current study is to swiftly find new treatments for the monkeypox virus using advanced computational approaches. By investigating five potential MPXV targets (DNA ligase, Palmytilated Extracellular Enveloped Virus (EEV) membrane protein, Scaffold protein D13, Thymidylate Kinase, and Viral core cysteine proteinase), this research was carried out using cutting-edge computational techniques against human monkeypox virus infection. Here we present the accurate 3D structures and their binding cavities of the selected targets with higher confidence using AlphaFold 2 and SiteMap analysis. Molecular docking and MD simulation analysis revealed the top five potential lead compounds with higher binding affinity and stability toward selected targets. Binding free energy calculations and other essential dynamics analysis supports the finding. The selected lead compounds utilizing virtual screening and drug repurposing approach reported in this study are beneficial for medical scientists and experimental biologists in drug development for the treatment of human MPXV.Communicated by Ramaswamy H. Sarma.

Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) by resveratrol derivatives in cancer therapy: in silico approach.

In a number of human cancers, both cycloxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are up-regulated and co-expressed, promoting cancer cell proliferation and angiogenesis. Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural polyphenolic phytoalexin found in a variety of plants that influences various signal-transduction pathways which control apoptosis, cell growth and cell division, metastasis, angiogenesis and inflammation, and has an impact on cancer stages ranging from initiation to progression. In this work, molecular docking and molecular dynamics simulation method are employed to design resveratrol derivatives for COX-2 and 5-LOX enzymes. By attaching several functional groups on four different places of the resveratrol scaffold, the R group enumeration approach was employed to build four libraries of resveratrol derivatives. Thus, R group enumeration is done to focus on the enhancement of potency of compounds and other chemical characteristics like solubility. Drug-like filters such as REOS 1, 2, 3 and PAINS were applied to the libraries, generating a total of 5557 compounds. Drug-like filters such as REOS and PAINS-1, 2 and 3 were applied to the libraries, generating a total of 5557 compounds. All of these compounds were docked with both enzymes using the Glide SP and XP docking methods. Enrichment calculations were performed using 40 compounds from XP docking along with resveratrol, and 1000 decoy compounds from the DUD-E database to validate the docking protocol. The stability of the complexes was further studied using molecular dynamics simulation, radius of gyration, MM/GBSA, H bond monitoring and electrostatic potential surface (EPS). ADMET properties of compounds were studied using SwissADME and pkCSM server.Communicated by Ramaswamy H. Sarma.

High throughput virtual screening and molecular dynamics simulation analysis of phytomolecules against BfmR of Acinetobacter baumannii: anti-virulent drug development campaign.

Acinetobacter baumannii is a notorious multidrug resistant bacterium responsible for several hospital acquired infections assisted by its capacity to develop biofilms. A. baumannii BfmR (RstA), a response regulator from the BfmR/S two-component signal transduction system, is the major controller of A. baumannii biofilm development and formation. As a result, BfmR represents a novel target for anti-biofilm treatment against A. baumannii. The discovery of the high-resolution crystal structure of BfmR provides a good chance for computational screening of its probable inhibitors. Therefore, in this study we aim to search new, less toxic, and natural BfmR inhibitors from 8450 phytomolecules available in the Indian Medicinal Plants, Phytochemistry and Therapeutic (IMPPAT) database by analyzing molecular docking against BfmR (PDB ID: 6BR7). Out of these 8450 phytomolecules 6742 molecules were successfully docked with BfmR with the docking score range -6.305 kcal/mol to +5.120 kcal/mol. Structure based-molecular docking (SB-MD) and ADMET (absorption, distribution, metabolism, excretion, & toxicity) profile examination revealed that Norepinephrine, Australine, Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline phytocompounds strongly binds to the active site residues of BfmR. Furthermore, molecular dynamics simulation (MDS) studies for 100 ns and the binding free energy (MM/GBSA) analysis elucidated the binding mechanism of Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline to BfmR. In summary, these phytocompounds seems to have the promising molecules against BfmR, and thus necessitates further verification by both in vitro and in vivo experiments. HighlightsBfmR plays a key role in biofilm development and exopolysaccharide (EPS) synthesis in A. baumannii.Computational approach to search for promising BfmR inhibitors from IMPAAT database.The lead phytomolecules such as Calystegine B3, 7,7 A-Diepialexine, and Alpha-Methylnoradrenaline displayed significant binding with BfmR active site.The outcome of BfmR binding phytomolecules has broadened the scope of hit molecules validation.Communicated by Ramaswamy H. Sarma.

4-Methylesculetin ameliorates LPS-induced depression-like behavior through the inhibition of NLRP3 inflammasome.

The pathophysiology of depression is heavily dependent on inflammation. Evidence suggests that the etiology of depression is linked with NLRP3 inflammasome-induced inflammation. Therefore, blocking the activated NLRP3 inflammasome may be beneficial for treating depression. Due to the limitations of currently available antidepressants, it is necessary to develop novel, safe, and affordable drugs for the treatment of depression. A natural coumarin derivative named 4-methylesculetin (4-MESC) possesses anti-inflammatory properties. However, the role of 4-MESC as an antidepressant has not been elucidated. Therefore, in this study, we explored the antidepressant-like effects of 4-MESC and its underlying molecular mechanism through the modulation of the NLRP3 inflammasome. The docking and molecular dynamic simulation studies revealed that 4-MESC has a higher affinity for the NLRP3 PYD. Blood-brain barrier permeability was confirmed using the SwissADME pharmacokinetic tool. High doses (50 mg/kg) of 4-MESC significantly reduced the immobility duration in the tail-suspension test (TST) and forced swim test (FST) without changing the overall locomotor activity in the female Swiss albino mice that were subjected to lipopolysaccharide (LPS). LPS-induced pro-inflammatory cytokines such as IL-6 and TNF-α were reduced in serum and brain tissues using 4-MESC. 4-MESC's neuroprotective effects are mediated by increased brain-derived neurotrophic factor (BDNF) and decreased cortisol levels. 4-MESC markedly reduced LPS-induced elevated levels of ROS and lipid peroxidation (malondialdehyde levels) and enhanced the superoxide dismutase (SOD) activity and glutathione levels, which revealed its anti-oxidant potential against oxidative stress. 4-MESC diminished the expression levels of NF-κBp65, IL-6, NLRP3, caspase-1, gasdermin D, and IL-1ß in the hippocampus. These findings demonstrated that 4-MESC exhibited antidepressant-like effects by inhibiting the NLRP3 inflammasome. However, other antidepressant mechanisms might also be involved which require further studies.

Identification of potential drug candidates as TGR5 agonist to combat type II diabetes using in silico docking and molecular dynamics simulation studies.

A cell surface bile acid receptor TGR5 being considered as a novel target for Type II diabetes found to be expressed in various tissues. A major role for TGR5 is to maintain blood sugar levels and increase in energy expenditure. These benefits make it a potential candidate for the treatment of type 2 diabetes, obesity and other metabolic disorder. To date, many novel TGR5 agonists have been synthesized and evaluated in the literature, but very few in silico computational studies have been reported. The discovery of a high-resolution crystal structure of TGR5 in 2020 provides an excellent opportunity for computational screening of potential agonists. In this study, we, therefore, aim to search novel, less toxic TGR5 agonists by iteratively analyzing molecular docking against TGR5 (PDB ID: 7CFN) by means of structure-based virtual screening. The docking score of the designed coumarin derivatives that have been docked successfully varies between -9.4 and -9.0 kcal/mol. The molecular docking and ADMET profile examinations of compounds D1, D5 and D15 revealed that these have a strong affinity for the active site residues of TGR5. In addition, molecular dynamics simulation (MDS) studies have shown the stability of compounds that bind to TGR5. It can be summarized that designed coumarin derivatives seem to have promising activity as TGR5 agonists.Communicated by Ramaswamy H. Sarma.

Exploring Potential Non-steroidal Aromatase Inhibitors for Therapeutic Application against Estrogen-dependent Breast Cancer.

BACKGROUND: Breast cancer is one of the most commonly diagnosed cancer types among women worldwide. Cytochrome P450 aromatase (CYP19A1) is an enzyme in vertebrates that selectively catalyzes the biosynthesis of estrogens from androgenic precursors. Researchers have increasingly focused on developing non-steroidal aromatase inhibitors (NSAIs) for their potential clinical use, avoiding steroidal side effects. OBJECTIVES: The objective of the present work is to search for potential lead compounds from the ZINC database through various in silico approaches. METHODS: In the present study, compounds from the ZINC database were initially screened through receptor independent-based pharmacophore virtual screening. These screened molecules were subjected to several assessments, such as Lipinski rule of 5, SMART filtration, ADME prediction using SwissADME and lead optimization. Molecular docking was further applied to study the interaction of the filtered compounds with the active site of aromatase. Finally, the obtained hit compounds, consequently represented to be ideal lead candidates, were escalated to the MD simulations. RESULTS: The results indicated that the lead compounds might be potential anti-aromatase drug candidate. CONCLUSION: The findings provided a valuable approach in developing novel anti-aromatase inhibitors for the treatment of ER+ breast cancer.

Pharmacoinformatics approach for the screening of Kovidra (Bauhinia variegata) phytoconstituents against tumor suppressor protein in triple negative breast cancer.

Globally, 2.3 million women were diagnosed with breast cancer, with 6,85000 mortalities in year 2021; making it the world's most prevalent cancer. This growing global burden necessitates a new treatment option, and plant-based medicines offers a promising alternative to conventional cancer treatment. In this work, screening of phytoconstituents of an indigenous therapeutic plant, Bauhinia variegata carried out for potential regulator of tumor suppressor protein p53. Here, an in-silico analysis was employed to develop more effective, pharmaceutically potent small drug-like compounds that target tumor suppressor protein p53. The methanol and aqueous powdered extracts of Bauhinia variegata were prepared and phytochemically evaluated along with antioxidant property evaluation. The LC50 of methanol (325.33 µg/ml) and aqueous extract (361.15 µg/ml) showed their cytotoxic characteristics. Further, GCMS analysis of both the extracts reveals total 57 secondary metabolites. Among these, four lead compounds; compound 1, compound 2, compound 3 and compound 4 were found to have the highest binding ability (-8.15 to -5.40 kcal/mol) with p53. MD simulation and binding free energy validates these findings with highest binding free energy (-67.09 ± 4.87 kcal/mol) towards p53 by the lead phytocompound 2. Selected compounds exhibit excellent pharmacokinetic features and drug-like characteristics. The acute toxicity (LD50) values of the lead phytocompounds ranges from 670 mg/kg to 3100 mg/kg, with toxicity classes of IV and V. As a result, these druggable phytochemicals could serve as potential lead applicants for triple negative breast cancer treatment. However, more in vitro and in vivo research is planned to produce future breast cancer medicine. HIGHLIGHTSScreening of phytoconstituents of an indigenous therapeutic plant, Bauhinia variegata, for potential regulator of tumor suppressor protein p53.The LC50 of methanol (325.33µg/ml) and aqueous extract (361.15µg/ml) showed their cytotoxic characteristics.GCMS analysis of both the extracts reveals total 57 secondary metabolites. Among these, four lead compounds were found to have the highest binding affinity (-8.153 to -5.401 kcal/mol) with tumor suppressor protein p53.MD simulation along with the Prime MM/GBSA binding free energy validates this discovery with highest binding free energy (-67.09 ± 4.87 kcal/mol) towards p53 by the lead compound 2.The acute toxicity (LD50) values of the lead phytocompounds ranges from 670 mg/kg to 3100 mg/kg, with toxicity classes of IV and V.As a result, these druggable phytochemicals could serve as potential lead applicants for triple negative breast cancer treatment.Communicated by Ramaswamy H. Sarma.