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.

Terpenoid phytocompounds from mangrove plant Xylocarpus moluccensis as possible inhibitors against SARS-CoV-2: In silico strategy.

COVID-19 shook the world during the pandemic, where the climax it reached was vaccine manufacturing at an unfathomable pace. Alternative promising solutions to prevent infection from SARS-CoV-2 and its variants will remain crucial in the years to come. Due to its key role in viral replication, the major protease (Mpro) enzyme of SARS-CoV-2 can be an attractive therapeutic target. In the present work, natural terpenoids from mangrove medicinal plant Xylocarpus moluccensis (Lam.) M. Roem. were screened using computational methods for inhibition of Mpro protein. Out of sixty-seven terpenoids, Angolensic acid methyl ester, Moluccensin V, Thaixylomolin F, Godavarin J, and Xylomexicanolide A were shortlisted based on their docking scores and interaction affinities (- 13.502 to - 15.52 kcal/mol). The efficacy was validated by the 100 ns molecular dynamics study. Lead terpenoids were within the acceptable range of RMSD and RMSF with a mean value of 2.5 Å and 1.5 Å, respectively indicating that they bound tightly within Mpro and there was minimal fluctuation and stability of Mpro upon binding of these terpenoids. The utmost favorable binding strengths as calculated by MM-GBSA, were of Angolensic acid methyl ester and Moluccensin V with binding free energies (ΔGbind) of - 39.084, and - 43.160 kcal/mol, respectively. The terpenoids showed no violations in terms of Drug Likeliness and ADMET predictions. Overall, the findings indicate that Angolensic acid methyl ester and Moluccensin V are effective terpenoids having strong binding interaction with Mpro protein, which must be tested in vitro as an effective anti-SARS-CoV-2 drug.

Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-ß-Cyclodextrin against Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin's clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-ß-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR-γ Partial Agonists by Modulating Epithelial-Mesenchymal Transition in Lung Cancer Metastasis.

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR-γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR-γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR-γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2-furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI-H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E-box binding homeobox 1) and concomitant upregulation of epithelial marker (E-cadherin).

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.

Free Fatty Acids from Cow Urine DMSO Fraction Induce Cell Death in Breast Cancer Cells without Affecting Normal GMSCs.

OBJECTIVE: The objective of this study was to explore the biological relevance of free fatty acids derived from cow urine DMSO fraction (CUDF) by employing in vitro and in silico approaches. BACKGROUND: Metabolic heterogeneity at the intra- and intercellular levels contributes to the metabolic plasticity of cancer cells during drug-induced response. Free fatty acid (FFA) availability at intra- and intercellular levels is related to tumor heterogeneity at interpatient and xeno-heterogeneity levels. METHODS: We collected fresh urine from healthy cows and subjected it to fractionation in DMSO using drying, vortexing, and centrifugation. Finally, the sterile filtrate of cow urine DMSO fraction (CUDF) was evaluated for antiproliferative and proapoptotic effects in MCF-7 and ZR-75-1 breast cancer cells using routine cell-based assays. Intracellular metabolites were studied with the help of a novel in-house vertical tube gel electrophoresis (VTGE) method to reveal the nature of CUDF components in MCF-7 cells. Identified intracellular FFAs were studied for their molecular interactions with targeted receptor histone deacetylase (HDAC) using molecular docking and molecular dynamics (MD) simulations. RESULTS: CUDF showed a significant reduction in cell viability and cell death in MCF-7 and ZR-75-1 breast cancer cells. Interestingly, FFAs tetracosanedioic acid, 13Z-docosenoic acid (erucic acid), nervonic acid, 3-hydroxy-tetradecanoic acid, and 3-hydroxcapric acid were found inside the treated MCF-7 cancer cells. These FFAs, including tetracosanedioic acid, indicated a specific affinity to HDAC at their inhibitory sites, similar to trichostatin A, a known inhibitor. CONCLUSIONS: This study reports on FFAs derived from CUDF as potential antiproliferative and pro-cell death agents against breast cancer cells. MD simulations hinted at tetracosanedioic acid and other FFAs as inhibitors of HDAC that could explain the observed effects of FFAs in cancer cells.

Computational docking investigation of phytocompounds from bergamot essential oil against Serratia marcescens protease and FabI: Alternative pharmacological strategy.

The rapid development of multi-drug resistant (MDR) pathogens adds urgency to search for novel and safe drugs having promising action on new and re-emerging infectious pathogens. Serratia marcescens is an MDR pathogen that causes several-healthcare associated infections. Curbing bacterial virulence, rather than inhibiting its growth, is a promising strategy to diminish the pathogenesis of infectious bacteria, reduce the development of antimicrobial resistance, and boost the host immune power to eradicate infections. Bergamot essential oil (BEO) is a remarkable source of promising therapeutics against pathogens. Therefore, the present investigation aimed to analyze the major phytocompounds from BEO against S. marcescens virulent proteins using in silico studies. The analysis of BEO phytocompounds was achieved by Gas chromatography-mass spectrometry (GC-MS) method. The molecular docking was carried out using the SP and XP docking protocol of the Glide program. The drug-likeness and pharmacokinetics properties (ADMET properties) were analyzed with SwissADME and pkCSM server. The results revealed that the major compounds present in BEO are Linalool (8.17%), D-Limonene (21.26%), and Linalyl acetate (26.91%). Molecular docking analysis revealed that these compounds docked strongly within the binding cavities of Serratia protease and FabI model which in turn curb the pathogenesis of this bacteria. Linalool interacted with the Serratia protease and FabI with a binding energy of - 3.130 kcal/mol and - 3.939 kcal/mol, respectively. Based on the pharmacokinetics findings all lead BEO phytocompounds appear to be promising drug candidates. Overall, these results represent a significant step in the development of plant-based compounds as a promising inhibitor of the virulent proteins of the MDR S. marcescens.

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.

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.

GC-MS profiling of Bauhinia variegata major phytoconstituents with computational identification of potential lead inhibitors of SARS-CoV-2 Mpro.

Severe acute respiratory syndrome coronavirus 2 was originally identified in Wuhan city of China in December 2019 and it spread rapidly throughout the globe, causing a threat to human life. Since targeted therapies are deficient, scientists all over the world have an opportunity to develop novel drug therapies to combat COVID-19. After the declaration of a global medical emergency, it was established that the Food and Drug Administration (FDA) could permit the use of emergency testing, treatments, and vaccines to decrease suffering, and loss of life, and restore the nation's health and security. The FDA has approved the use of remdesivir and its analogs as an antiviral medication, to treat COVID-19. The primary protease of SARS-CoV-2, which has the potential to regulate coronavirus proliferation, has been a viable target for the discovery of medicines against SARS-CoV-2. The present research deals with the in silico technique to screen phytocompounds from a traditional medicinal plant, Bauhinia variegata for potential inhibitors of the SARS-CoV-2 main protease. Dried leaves of the plant B. variegata were used to prepare aqueous and methanol extract and the constituents were analyzed using the GC-MS technique. A total of 57 compounds were retrieved from the aqueous and methanol extract analysis. Among these, three lead compounds (2,5 dimethyl 1-H Pyrrole, 2,3 diphenyl cyclopropyl methyl phenyl sulphoxide, and Benzonitrile m phenethyl) were shown to have the highest binding affinity (-5.719 to -5.580 kcal/mol) towards SARS-CoV-2 Mpro. The post MD simulation results also revealed the favorable confirmation and stability of the selected lead compounds with Mpro as per trajectory analysis. The Prime MM/GBSA binding free energy supports this finding, the top lead compound 2,3 diphenyl cyclopropyl methyl phenyl sulphoxide showed high binding free energy (-64.377 ± 5.24 kcal/mol) towards Mpro which reflects the binding stability of the molecule with Mpro. The binding free energy of the complexes was strongly influenced by His, Gln, and Glu residues. All of the molecules chosen are found to have strong pharmacokinetic characteristics and show drug-likeness properties. The lead compounds present acute toxicity (LD50) values ranging from 670 mg/kg to 2500 mg/kg; with toxicity classifications of 4 and 5 classes. Thus, these compounds could behave as probable lead candidates for treatment against SARS-CoV-2. However further in vitro and in vivo studies are required for the development of medication against SARS-CoV-2.

Antioxidant, anti-quorum sensing, biofilm inhibitory activities and chemical composition of Patchouli essential oil: in vitro and in silico approach.

The interest in naturally occurring essential oils from medicinal plants has increased extremely over the last decade markedly because they possess antimicrobial and antioxidant protective properties against different chronic diseases. Extensive survival of drug-resistant infectious bacteria depends on quorum sensing (QS) signaling network which raises the need for alternative antibacterial compounds. The aim of this study was to examine the phytochemical compounds of patchouli essential oil (PEO) and to assess its antioxidant activity. Antioxidant studies estimated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging method showed that the PEO has effective antioxidant activity (IC50 19.53 µg/mL). QS inhibitory activity of PEO was examined by employing the biosensor strain, Chromobacterium violaceum CV12472. At sub-lethal concentrations, PEO potentially reduced the QS regulated violacein synthesis in CV12472 without inhibiting its cell proliferation. Moreover, it also effectively reduced the production of some QS regulated virulence factors and biofilm development in P. aeruginosa PAO1 without hindering its growth. Phytochemical analysis of PEO was done by GC/MS technique. Molecular docking of PEO major compounds with QS (LasR and FabI) and biofilm regulator proteins (MvfR and Sialidase) of PAO1 was evaluated. These phytocompounds showed potential hydrogen binding interactions with these proteins. The overall results, in vitro and in silico, suggest that PEO could be applied as biocontrol agent against antibiotic resistance pathogens. Communicated by Ramaswamy H. Sarma.

Probing intermolecular interactions and binding stability of kaempferol, quercetin and resveratrol derivatives with PPAR-γ: docking, molecular dynamics and MM/GBSA approach to reveal potent PPAR- γ agonist against cancer.

Peroxisome Proliferator-Activated Receptors-γ (PPAR-γ), a ligand-activated transcription factor, suggested having anti-inflammatory effects by activating the target genes when bound to the ligand. Herein, we examined a conformational analysis of 8708 derivatives of Kaempferol, Quercetin, and Resveratrol, the prime activators of PPAR-γ molecular target by employing molecular docking and dynamic simulation pipeline to screen out potential agonists. The structure-based docking procedure performed by FlexX tool shortlisted high binding affinities of these derivatives of Kaempferol, Quercetin and Resveratrol with the protein receptor with a score of -38.94 kcal/mol (4'-Carboxy-5, 7-Dihydroxyflavone-CDHF), -41.63 kcal/mol (Demethyltorosaflavone D- DMTF) and -31.52 kcal/mol (Resveratrol-O-disulphate- RD) respectively, signifying the selected derivatives forms interactions like H-bond, Aromatic H-Bond, Pi-Pi stacking and salt bridges with PPAR-γ. The PPAR-γ-derivative complex was stabilized by intermolecular hydrogen bonds and stacking interactions. A greater interaction was significantly observed between the binding affinities of derivatives compared to the standards. Based on the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) carried by the means of high-speed molecular dynamics (MD) and simulation of best-docked poses, the ligand, DMTF attained the most favored interaction with PPAR-γ. Thus, it appeared to have high chemical scaffold diversity and may confer high drug-likeness. The binding free energy (ΔG) led us to manifest Quercetin derivative to have a key role for PPAR-γ receptor. The result obtained clearly indicates the exploitation of the promising new drug leads that may further influence in synthesizing and analyzing the development as anti-cancer agonists.Communicated by Ramaswamy H. Sarma.

Detection of Nail Oncometabolite SAICAR in Oral Cancer Patients and Its Molecular Interactions with PKM2 Enzyme.

Oncometabolites are known to drive metabolic adaptations in oral cancer. Several oncometabolites are known to be shared between cancer cells and non-cancer cells including microbiotas to modulate the tumor microenvironment. Among potential oncometabolites, succinylaminoimidazolecarboxamide ribose5'-phosphate (SAICAR) supports the growth and invasiveness of cancer cells by pyruvate kinase M2 (PKM2) enzyme in a glucose starved tumor microenvironment. There is a significant gap that shows the detection of SAICAR in biological samples including nails of oral cancer patients. Metabolite identification of SAICAR was investigated in the nails of oral cancer patients using novel vertical tube gel electrophoresis (VTGE) and LC-HRMS. Further molecular docking and molecular dynamics simulations (MDS) were employed to determine the nature of molecular interactions of SAICAR (CHEBI ID:18319) with PKM2 (PDB ID: 4G1N). Molecular docking of SAICAR (CHEBI ID:18319) was performed against pyruvate kinase M2 (PDB ID: 4G1N). Data suggest the presence of oncometabolite SAICAR in nails of oral cancer. Molecular docking of SAICAR with PKM2 showed appreciable binding affinity (-8.0 kcal/mol) with residues including ASP407, THR405, GLU410, ARG443, GLY321, ARG436, HIS439, LYS266, and TYR466. Furthermore, MDS confirmed the specific binding of SAICAR within the activator site of PKM2 and the stability of SAICAR and PKM2 molecular interactions. In conclusion, SAICAR is a promising oncometabolite biomarker present in the nails of oral cancer patients. A significant activation potential of SAICAR exists with the PKM2 enzyme.

In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19.

The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 Mpro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 Mpro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the Mpro cavity and thus having conformational stability. Glutamic acid (Glu166) of Mpro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 Mpro.

Exploring conformational changes of PPAR-Ɣ complexed with novel kaempferol, quercetin, and resveratrol derivatives to understand binding mode assessment: a small-molecule checkmate to cancer therapy.

Peroxisome proliferator-activated receptors-γ (PPAR-γ), a ligand-activated transcription factor, activated by several ligands like fatty acids (linoleic acid being the most common) or their metabolites, can function as potential therapeutic target for various cancers. Although various synthetic ligands, thiazolidinediones (TZDs), serves as full agonist for PPAR-γ, application of these molecules has been discontinued due to adverse toxicity profile. Hence, with a dire need to identify novel PPAR-γ-agonists, the present in silico study aimed to determine the effectiveness of potent flavonoids, kaempferol (CID: 5280863), quercetin (CID: 5280343), and stilbenoid resveratrol (CID: 445154) and their 806 derivatives towards PPAR-γ that could combat the deleterious effect of TZDs. The molecular docking experiment performed by FlexX elucidated the efficacy of derivatives; Kem204, Qur8, and Res183 of kaempferol, quercetin, and resveratrol respectively to be more effective against PPAR-γ as compared with other derivatives. The physicochemical and pharmacokinetic parameters of Kem204, Qur8, and Res183 follow the drug-likeness and thus comprise a pharmacologically active model to be considered for advancing further potential hits. Further molecular dynamics (MD) simulation study revealed the Qur8 compound to have favorable dynamic interactions within the PPAR-γ which certainly paves away in developing futuristic potential anticancer drugs. Graphical abstract.

Data on docking of phytoconstituents of Actinidia deliciosa on dengue viral targets.

Major Phytoconstituents of Actinidia deliciosa were explored for their anti-viral potential against dengue virus (DENV). The docking of these phytoconstituents was performed on 7 viral targets- 4 DENV non structural protein (NS5-SAM binding domain, NS5 RdRp domain, NS3 helicase & NS2B-NS3 protease) and 3 DENV structural proteins (Envelope protein-ß-OD domain, stem domain & Domain III). The analysis was done on the basis of binding affinity, type of interactions (bond type and distance) and interaction with amino acids significant in viral replication. The top 5 phytoconstituents with best docking score have been reported.

Molecular interaction studies of Deguelin and its derivatives with Cyclin D1 and Cyclin E in cancer cell signaling pathway: The computational approach.

Deguelin is a major active ingredient and principal component in several plants and it is a potential molecule to target proteins of cancer cell signaling pathway. As a complex natural extract, deguelin interacts with various molecular targets to exert its anti-tumor properties at nanomolar level. It induces cell apoptosis by blocking anti-apoptotic pathways, while inhibiting tumor cell multiplication and malignant transformation through p27-cyclin-E-pRb-E2F1- cell cycle control and HIF-1alphaVEGF antiangiogenic pathways. In silico studies of deguelin and its derivatives is performed to explore interactions with Cyclin D1 and Cyclin E to understand the molecular insights of derivatives with the receptors. Deguelin and its derivatives are minimized by Avogadro to achieve stable conformation. All docking simulation are performed with AutoDockVina and virtual screening of docked ligands are carried out based on binding energy and number of hydrogen bonds. Molecular dynamics (MD) and Simulation of Cyclin D1 and Cyclin E1 is performed for 100 ns and stable conformation is obtained at 78 ns and 19 ns respectively. Ligands thus obtained from docking studies may be probable target to inhibit cancer cell signaling pathways.

Molecular Modeling, Docking, Dynamics and Simulation of Gefitinib and its Derivatives with EGFR in Non-small Cell Lung Cancer.

BACKGROUND: Gefitinib (lressa) is the most prescribed drug, highly effective to treat nonsmall cell lung cancer; primarily it was considered that targeted therapy is a kinase inhibitor. The nonsmall cell lung cancer is caused by mutation in the Epithelial Growth Factor Receptor (EGFR) gene. Iressa works by blocking the EGFR protein that helps the cancer cell growth. EGFR protein has lead to the development of anticancer therapeutics directed against EGFR inhibitor including Gefitinib for non-small cell lung cancer. METHODS: To explore the interaction between Gefitinib and its derivatives with crystal structure of EGFR to understand the better molecular insights interaction strategies. Molecular modeling of ligands (Gefitinib and its derivatives) was carried out by Avogadro software till atomic angle stable confirmation was obtained. The partial charges for the ligands were assigned as per standard protocol for molecular docking. All docking simulations were performed with AutoDockVina. Virtual screening was carried out based on binding energy and hydrogen bonding affinity. Molecular dynamics (MD) and Simulation EGFR were done using GROMACS 5.1.1 software to explore the interaction stability in a cell. RESULTS: The stable conformation for EGFR protein trajectories were captured at various time intervals 0-20ns. Few compounds screen based on high affinity as the inhibitor for EGFR may inhibit the cell cycle signaling in non-small cell lung cancer. CONCLUSION: These result suggested a computer-aided screening approach of Gefitinib derivatives with regard to their binding to EGFR for identifying novel drugs for the treatment of non-small cell lung cancer.

In vivo and molecular docking studies using whole extract and phytocompounds of Aegle marmelos fruit protective effects against Isoproterenol-induced Myocardial infarction in rats.

Myocardial infarction (MI) is a leading major health problem with increased morbidity and mortality worldwide. The present study investigates isoproterenol (ISO) induced MI and the beneficial role of Aegle marmelos fruit extract (AMFE) in rats. Our results indicated the significant augmentation of plasma nitric oxide (NOx) levels, C-reactive protein (CRP), homocysteine, apolipoprotein B (apo-B), cardiac tissue lipid peroxidation and liver 3-hydroxy-3 methyl glutaryl CoA (HMG-CoA) reductase activity in ISO treated rats (85mg/kg b.wt) with a concomitant decrease in plasma apolipoprotein A1 (apo-A), lipase activity, paraoxonase-1 activity and cardiac tissue taurine levels when compared with controls. However, pretreatment of ISO administered rats with AMFE (150mg/kg b.wt/day for 45 days) markedly brought the observed alterations toward near normal level indicating its protective role against MI. Further, we have extended our studies to study the interaction of important phytocompounds, marmesin, marmin, umbelliferone and impertonin, present in AMFE with key enzymes, HMG-CoA reductase, iNOS, lipoprotein lipase and paraoxonase using AutoDock4. Molecular docking analysis indicated that HMG-CoA reductase, inducible nitric oxide synthase (iNOS) and lipoprotein lipase formed a strong enzyme ligand complex with impertonin. While the marmesin showed strong interaction with paraoxonase enzyme. In conclusion, our results suggest that AMFE acts as a strong protective agent against ISO-induced MI, and the bioactive compounds are responsible for this protective action which is confirmed by molecular docking studies.