A systematic review on understanding the mechanistic pathways and clinical aspects of natural CDK inhibitors on cancer progression.: Unlocking cellular and biochemical mechanisms.

Cell division, differentiation, and controlled cell death are all regulated by phosphorylation, a key biological function. This mechanism is controlled by a variety of enzymes, with cyclin-dependent kinases (CDKs) being particularly important in phosphorylating proteins at serine and threonine sites. CDKs, which contain 20 unique components, serve an important role in regulating vital physiological functions such as cell cycle progression and gene transcription. Methodologically, an extensive literature search was performed using reputable databases such as PubMed, Google Scholar, Scopus, and Web of Science. Keywords encompassed "cyclin kinase," "cyclin dependent kinase inhibitors," "CDK inhibitors," "natural products," and "cancer therapy." The inclusion criteria, focused on relevance, publication date, and language, ensured a thorough representation of the most recent research in the field, encompassing articles published from January 2015 to September 2023. Categorization of CDKs into those regulating transcription and those orchestrating cell cycle phases provides a comprehensive understanding of their diverse functions. Ongoing clinical trials featuring CDK inhibitors, notably CDK7 and CDK4/6 inhibitors, illuminate their promising potential in various cancer treatments. This review undertakes a thorough investigation of CDK inhibitors derived from natural (marine, terrestrial, and peptide) sources. The aim of this study is to provide a comprehensive comprehension of the chemical classifications, origins, target CDKs, associated cancer types, and therapeutic applications.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

Biopolymer based film loaded with Cholecalciferol: A novel technique to enhance nutritional supplement absorbance.

In terms of delivery systems for active compounds, orally disintegrating films are a great option. The initial stage in creating an oral disintegrating film is selecting a film-forming polymer. The basic polymers combination Microcrystalline Cellulose (MCC), which is co-processed with Carboxymethylcellulose Sodium (CMC) and hydroxypropylmethyl cellulose were used to create an oral disintegrating film that contains cholecalciferol (Vitamin D3), a fat-soluble vitamin that aids in the body's absorption of calcium and phosphorus. The goal of the current inquiry was to develop orally disintegrating films of vitamin D3 to improve patient comfort and compliance for pediatric or elderly patients due to its simplicity of administration. Films containing drugs and made of the appropriate plasticizer and chosen polymers demonstrated outstanding film forming and folding endurance. The dissolution test showed that Vitamin D3 has a rapid disintegration property, with the majority of it dissolving in the medium (pH 6.8) in less than two minutes after being inserted. To verify that the films were successfully formed, a variety of procedures including HPLC, FT-IR and microscopic studies were employed. When kept at 40oC with humidity of 75%, the film showed good stability for at least three months.

Phytochemical profiling, in vitro biological activity, docking studies, and cytotoxicity assessments of Rondeletia odorata Jacquin: An unexplored plant of the coffee family.

Rondeletia odorata Jacquin is a flowering plant that belongs to the coffee family. As a rich source of polyphenols with significant antioxidant potential, R. odorata may have health benefits. Therefore, in the current work, ethanolic extract of aerial parts and its n-hexane, ethyl acetate, and n-butanol soluble fractions were analyzed for their antioxidant potential and various enzyme inhibition properties. The total phenolic and flavonoid contents of the crude ethanol extract (ROE) and its n-hexane (ROH), ethyl acetate (ROEA), and n-butanol (ROB) fractions were determined spectrophotometrically, while metabolic profiling was established through UHPLC-MS analysis, which revealed the presence of 58 phytochemicals. Total phenolic and flavonoid contents of ROE extract were measured as 51.92 mg GA.Eq./g of dry extract and 52.35 mg Qu.Eq./g of the dry extract, respectively. In the DPPH radical scavenging activity assay, ROE and ROEA showed the highest potential with values of 62.13 ± 0.62 and 76.31% ± 1.86%, respectively, comparable to quercetin (80.89% ± 0.54%). Similarly, in the FRAP assay, the same pattern of the activity was observed with ROE and ROEA, which displayed absorbance values of 1.32 ± 0.01 and 0.80 ± 0.02 at 700 nm, respectively, which are comparable (1.76 ± 0.02) with the reference compound quercetin, whereas the ROH showed maximum metal-chelating capacity (62.61% ± 1.01%) among all extracts and fractions. Antibacterial activity assay indicated that the ROEA fraction was the most active against Serratia marcescens, Stenotrophomonas maltophilia, Bacillus subtilis, Klebsiella pneumonia, and Staphylococcus aureus, while the rest of the fractions showed good to moderate activity. Enzyme inhibition assays showed that ROEA fraction exhibited the highest activity with IC50 values of 2.78 ± 0.42 and 3.95 ± 0.13 mg/mL against urease and carbonic anhydrase (CA), respectively. Furthermore, the docking studies of some of the major compounds identified in the extract revealed a strong correlation with their inhibitory activity. All extracts and fractions were also tested for their thrombolytic activity, and the ROB fraction showed a notable potential. Antiviral assay led to remarkable outcomes. Thus, it can be inferred that aerial parts of R. odorata are potential sources of bioactive components with several significant pharmacological activities.

Comprehensive Phytochemical Profiling, Biological Activities, and Molecular Docking Studies of Pleurospermum candollei: An Insight into Potential for Natural Products Development.

The purpose of this study was to find the biological propensities of the vegetable plant Pleurospermum candollei by investigating its phytochemical profile and biological activities. Phytochemical analysis was done by spectroscopic methods to investigate the amount of total polyphenols, and biological evaluation was done by the different antioxidant, enzyme inhibitory (tyrosinase, α-amylase, and α-glucosidase), thrombolytic, and antibacterial activities. The highest amount of total phenolic and flavonoid contents was observed in methanolic extract (240.69 ± 2.94 mg GAE/g and 167.59 ± 3.47 mg QE/g); the fractions showed comparatively less quantity (57.02 ± 1.31 to 144.02 ± 2.11 mg GAE/g, and 48.21 ± 0.75 to 96.58 ± 2.30 mg QE/g). The effect of these bioactive contents was also related to biological activities. GCMS analysis led to the identification of bioactive compounds with different biological effects from methanolic extract (antioxidant; 55.07%, antimicrobial; 56.41%), while the identified compounds from the n-hexane fraction with antioxidant properties constituted 67.86%, and those with antimicrobial effects constituted 82.95%; however, the synergetic effect of polyphenols may also have contributed to the highest value of biological activities of methanolic extract. Molecular docking was also performed to understand the relationship of identified secondary metabolites with enzyme-inhibitory activities. The thrombolytic activity was also significant (40.18 ± 1.80 to 57.15 ± 1.10 % clot lysis) in comparison with streptokinase (78.5 ± 1.53 to 82.34 ± 1.25% clot lysis). Methanolic extract also showed good activity against Gram-positive strains of bacteria, and the highest activity was observed against Bacillus subtilis. The findings of this study will improve our knowledge of phytochemistry, and biological activities of P. candollei, which seems to be a ray of hope to design formulations of natural products for the improvement of health and prevention of chronic diseases; however, further research may address the development of novel drugs for use in pharmaceuticals.

Efficacy of Phytochemicals Derived from Roots of Rondeletia odorata as Antioxidant, Antiulcer, Diuretic, Skin Brightening and Hemolytic Agents-A Comprehensive Biochemical and In Silico Study.

Roots of Rondeletia odorata are a rich source of phytochemicals with high antioxidant potential and thus may possess health benefits. This study used the LC-MS technique to identify phytoconstituents in R. odorata roots extract/fractions. Results revealed that n-butanol fraction and ethanolic extract contained total phenolic and flavonoid contents with values of 155.64 ± 0.66 mgGAE/g DE and 194.94 ± 0.98 mgQE/g DE, respectively. Significant potential of antioxidants was observed by DPPH, CUPRAC and FRAP methods while the ABTS method showed moderate antioxidant potential. Maximum % inhibition for urease, tyrosinase and carbonic anhydrase was shown by ethanolic extract (73.39 ± 1.11%), n-butanol soluble fraction (80.26 ± 1.59%) and ethyl acetate soluble fraction (76.50 ± 0.67%) which were comparable with thiourea (standard) (98.07 ± 0.74%), kojic acid (standard) (98.59 ± 0.92%) and acetazolamide (standard) (95.51 ± 1.29%), respectively, while all other extract/fractions showed moderate inhibition activity against these three enzymes. Hemolytic activity was also observed to range from 18.80 ± 0.42 to 3.48 ± 0.69% using the standard (triton X-100) method. In total, 28 and 20 compounds were identified tentatively by LC-MS analysis of ethanolic extract and n-butanol soluble fraction, respectively. Furthermore, molecular docking was undertaken for major compounds identified by LC-MS for determining binding affinity between enzymes (urease, tyrosinase and carbonic anhydrase) and ligands. It was concluded that active phytochemicals were present in roots of R. odorata with potential for multiple pharmacological applications and as a latent source of pharmaceutically important compounds. This should be further explored to isolate important constituents that could be used in treating different diseases.

Phytochemical Profiling, Antioxidant, Anti-Inflammatory, Thrombolytic, Hemolytic Activity In Vitro and In Silico Potential of Portulacaria afra.

The use of complementary herbal medicines has recently increased in an attempt to find effective alternative therapies that reduce the adverse effects of chemical drugs. Portulacaria afra is a rich source of phytochemicals with high antioxidant activity, and thus may possess health benefits. This study used the latest developments in GC-MS coupling with molecular docking techniques to identify and quantify the phytoconstituents in P. afra tissue extracts. The results revealed that n-butanol P. afra (BUT-PA) dry extracts contained total phenolic and flavonoids contents of 21.69 ± 0.28 mgGAE/g and 196.58 ± 6.29 mgGAE/g, respectively. The significant potential of antioxidants was observed through CUPRIC, FRAP, and ABTS methods while the DPPH method showed a moderate antioxidants potential for P. afra. Enzymatic antioxidants, superoxide dismutase, peroxidase and catalase also showed a better response in the BUT-PA dry extracts. The thrombolytic activity of the BUT-PA extracts ranged from 0.4 ± 0.32 to 11.2 ± 0.05%. Similarly, hemolytic activity ranged from 5.76 ± 0.15 to 9.26 ± 0.15% using the standard (triton x) method. The BUTPA and CHPA showed moderate acetylcholinesterase and butrylcholinesterase inhibition, ranging from 40.78 ± 0.52 to 58.97 ± 0.33, compared to galantamine. The carrageenan induced hind-paw edema assay, while BUT-PA extracts showed anti-inflammatory properties in a dose-dependent manner. Furthermore, 20 compounds were identified in the BUTPA extracts by GC-MS. Molecular docking was performed to explore the synergistic effect of the GC-MS-identified compounds on COX-1 and COX-2 inhibition. A high binding affinity was observed for Stigmastan-3, 5-diene, Phthalic acid, 3. Alpha-Hydroxy-5, 16-androstenol. The computed binding energies of the compounds revealed that all the compounds have a synergistic effect, preventing inflammation. It was concluded that active phytochemicals were present in P. afra, with the potential for multiple pharmacological applications as a latent source of pharmaceutically important compounds. This should be further explored to isolate secondary metabolites that can be employed in the treatment of different diseases.