The peels extracted from various citrus species are major source of phenols, flavonoids and anti-microbial agents. The purpose of this study was a detailed investigation of the phytochemical and pharmacological character of the ethanolic (80%), methanolic and acetone extracts of the peel of local variants of orange (lemon, grape fruit, mousami, fruiter, and shikri malta). The extracts were studied to find out the total phenolic contents (TPC), and total flavonoids (TF) present. The antioxidant activities were assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging effect, and the reducing power was determined through free radical scavenging activity (FRAP) assays. The sensitivity of four bacterial strains to peels extracts was examined by applying the diffusion disc on agar medium method. It was found that ethanol was the best extracting agent for TPC and TF in fruit peels under study. The highest TPC (21.33 ± 0.06 mg GAE/g) was quantified in orange peels, whereas fruiter contained the lowest TPC (20.40 ± 0.03 mg GAE/g) in ethanolic extract. The highest amount of TF (2.02 ± 0.08 mg QE/g) was quantified in lemon peels, whereas shikri malta contained lowest quantity of TF (1.04 ± 0.02 mg QE/g). The highest free radical scavenging activity (93.1%) of DPPH was exhibited by lemon peels, whereas the least activity (78.6%) was shown by mousami peels. Ethanolic extract of orange peels demonstrated more reducing power while showing an absorption of 1.98, followed by methanolic (1.11) and acetone (0.81) extracts. The inhibition effect of methanolic extract of lemon peels (inhibition zone = 18 mm) against B. subtilis was considerable and comparable to that of ciprofloxacin. Gas chromatography/mass spectrometry (GC/MS) was used to detect the compounds in ethanolic extract and up to 14 compounds were detected. These compounds were also assessed for their docking scores. Plausible binding modes with polyphenol oxidase and four best compounds were selected for molecular dynamics (MD) simulation to analyze their structural stability with receptor.

Curcumin is an extensively studied natural compound due to its extensive biological applications. However, there are some drawbacks linked to this compound such as poor absorption, low water-solubility, quick systemic elimination, fast metabolism, poor pharmacokinetics, low bioavailability, low penetration targeting efficacy and low stability. To overcome these drawbacks, curcumin is encapsulated in nano-carriers. In the current studies, we synthesized nanoparticles of curcumin without using nanocarriers by different methods such as nano-suspension (Cur-NSM), sonication (Cur-SM) and anti-solvent precipitation (Cur-ASP) to enhance the solubility of curcumin in water. The prepared nanoparticles were characterized by FTIR, SEM and XRD analysis. These curcumin nanoparticles were screened for their solubilities in water, DPPH scavenging, amylase, α-glucosidase and β-glucosidase enzymatic activities. The particle size of nano-curcumin was found to be in the 47.4–98.7 nm range. The reduction in particle size of curcumin dramatically increases its solubility in water to 79.2 μg mL⁻¹, whereas the solubility of curcumin is just 0.98 μg mL⁻¹. Cur-ASP showed the highest free radical scavenging potential (48.84 ± 0.98%) which was comparable with standard BHT (50.48 ± 1.11%) at 75.0 μg mL⁻¹. As well, Cur-ASP showed the highest inhibition of α-amylase (68.67 ± 1.02%), α-glucosidase (58.30 ± 0.52%), and β-glucosidase (64.80 ± 0.43%) at 100 μg mL⁻¹ which is comparable with standard drug acarbose. The greater surface area of nanoparticles exposes the various groups of curcumin for blocking the binding sites of enzymes. This strategy may be helpful in designing curcumin as a potent therapeutic agent against diabetes mellitus. Further, the molecular interactions of curcumin with α-amylase, α-glucosidase, β-glucosidase, and polyphenol oxidase were assessed by analyzing the plausible binding modes of curcumin in the binding pocket of each receptor. The best binding mode of curcumin was used to make complexes with the target proteins and their stability was confirmed by 50 ns MD simulation.

Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process and ultimately helps to control the postprandial hyperglycemia. Diversified 2-(3-(3-methoxybenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides were synthesized and evaluated for their in vitro inhibitory potential against α-glucosidase and α-amylase enzymes. The compounds with chloro, bromo and methyl substituents demonstrated good inhibition of α-glucosidase enzymes having IC₅₀ values in the range of 25.88–46.25 μM, which are less than the standard drug, acarbose (IC₅₀ = 58.8 μM). Similarly, some derivatives having chloro, bromo and nitro substituents were observed potent inhibitors of α-amylase enzyme, with IC₅₀ values of 7.52 to 15.06 μM, lower than acarbose (IC₅₀ = 17.0 μM). In addition, the most potent compound, N-(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)acetamide (12i), was found to be a non-competitive and competitive inhibitor of α-glucosidase and α-amylase enzymes, respectively, during kinetic studies. The molecular docking studies provided the binding modes of active compounds and the molecular dynamics simulation studies of compound 12i in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies.

Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r²), correlation coefficient of leave-one-out cross-validation (q²), Fisher’s test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q² = 0.583, Predr² = 0.751) and CoMSIA (q² = 0.690, Predr² = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.