Novel α-amylase and α-glucosidase inhibitors from selected Nigerian antidiabetic plants: an in silico approach

Glucokinase activators are considered as new therapeutic arsenals that bind to the allosteric activator sites of glucokinase enzymes, thereby maximizing its catalytic rate and increasing its affinity to glucose. This study was designed to identify potent glucokinase activators from prenylated flavonoids isolated from medicinal plants using molecular docking, molecular dynamics simulation, density functional theory, and ADMET analysis. Virtual screening was carried out on glucokinase enzymes using 221 naturally occurring prenylated flavonoids, followed by molecular dynamics simulation (100 ns), density functional theory (B3LYP model), and ADMET (admeSar 2 online server) studies. The result obtained from the virtual screening with the glucokinase revealed arcommunol B (−10.1 kcal/mol), kuwanon S (−9.6 kcal/mol), manuifolin H (−9.5 kcal/mol), and kuwanon F (−9.4 kcal/mol) as the top-ranked molecules. Additionally, the molecular dynamics simulation and MM/GBSA calculations showed that the hit molecules were stable at the active site of the glucokinase enzyme. Furthermore, the DFT and ADMET studies revealed the hit molecules as potential glucokinase activators and drug-like candidates. Our findings suggested further evaluation of the top-ranked prenylated flavonoids for their in vitro and in vivo glucokinase activating potentials.

In an effort to design and synthesize a new class of α-glucosidase and α-amylase inhibitors, we have synthesized novel pyrrole based molecules using molecular hybridization approach. These novel analogs were synthesized by the novel methodology developed in our lab which comprises of the multi-component direct synthesis route using hypervalent iodine reagent. The compounds were characterized by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR and Mass Spectroscopy. These compounds were screened for their α-amylase and α- glucosidase activity. They showed a varying degree of inhibition with IC50 values ranging between 0.4 to 4.14 µmol/mL and 0.8 to 4.14 µmol/mL for α-amylase and α-glucosidase respectively. Compounds 3, 7, 12, and 18 showed excellent activity as compared to standard acarbose. This has identified a new class of α-amylase and α-glucosidase inhibitor which can be further developed as antihyperglycemic agents. The molecular docking analysis was carried out to better understand of interaction between α-amylase and α-glucosidase target and inhibitors in this series. We also generated a homology model for human α-glucosidase enzyme and identified the key residues at the binding site. The outcome of the study could be used for the rational design of potent and selective α-amylase and α-glucosidase inhibitors, respectively.

A Computational approach to discover potential quinazoline derivatives against CDK4/6 kinase

Despite the intensive research efforts towards antiviral drug against COVID-19, no potential drug or vaccines has not yet discovered. Initially, the binding site of COVID-19 main protease was predicted which located between regions 2 and 3. Structure-based virtual screening was performed through a hierarchal mode of elimination technique after generating a grid box. This led to the identification of five top hit molecules that were selected on the basis of docking score and visualization of non-bonding interactions. The docking results revealed that the hydrogen bonding and hydrophobic interactions are the major contributing factors in the stabilization of complexes. The docking scores were found between −7.524 and −6.711 kcal/mol indicating strong ligand-protein interactions. Amino acid residues Phe140, Leu141, Gly143, Asn142, Thr26, Glu166 and Thr190 (hydrogen bonding interactions) and Phe140, Cys145, Cys44, Met49, Leu167, Pro168, Met165, Val42, Leu27 and Ala191 (hydrophobic interactions) formed the binding pocket of COVID-19 main protease. From identified hits, ZINC13144609 and ZINC01581128 were selected for atomistic MD simulation and density functional theory calculations. MD simulation results confirm that the protein interacting with both hit molecules is stabilized in the chosen POPC lipid bilayer membrane. The presence of lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) in the hydrophobic region of the hit molecules leads to favorable ligand-protein contacts. The calculated pharmacokinetic descriptors were found to be in their acceptable range and therefore confirming their drug-like properties. Hence, the present investigation can serve as the basis for designing and developing COVID-19 inhibitors. Communicated by Ramaswamy H. Sarma

Background: The use of medicinal plants as supplemental or alternative medicine is widespread around the world. For the development of new drugs, studies on these medicinal plants that include pharmacological and toxicological assessments are crucial. Objective: This work aimed to find the total phenolic and flavonoid content, antioxidant, antibacterial, and antidiabetic potential of the traditionally used medicinal plant Mimosa rubicaulis Lam. Methods: The in vitro antidiabetic potential of methanolic extract and its fractions of the roots of M. rubicaulis were performed via enzyme (α-glucosidase and α-amylase) inhibition assays. Antioxidant and anti-inflammatory activities were carried out using 2,2 Diphenyl-1-picrylhydrazyl (DPPH), and reactive oxygen species (ROS) inhibiting methods. Well diffusion method is applied for antibacterial activity. Results: The crude extract reported the highest inhibition activity against α-glucosidase with an IC50 value of 10.29 ± 0.35 μg/mL compared to the standard acarbose’s IC50 value of 5.653 ± 0.29 μg/mL. Similarly, the ethyl acetate (EA) fraction disclosed significant inhibition against α-amylase with an IC50 value of 108.7 ± 0.66 μg/mL compared to the standard acarbose’s IC50 value of 6.01 ± 0.14 μg/mL. Likewise, the EA fraction showed the maximum antioxidant activity with an IC50 value of 11.89 ± 1.05 μg/mL among the crude extract and its fractions. Conclusion: Mimosa rubicaulis was found to have α-glucosidase and α-amylase inhibition, antiinflammatory, and antibacterial activity. To the best of our knowledge, this is the first report of α- glucosidase and α-amylase inhibition activity of this plant. Further studies on this plant are required to isolate potent compounds.

Anthocyanins are components of the flavonoid group with different properties, such as antidiabetic properties. This study aimed to isolate anthocyanin from Berberis integerrima Bunge fruits and evaluate α-amylase and α-glucosidase inhibition by this mentioned anthocyanin. The anthocyanin of Berberis integerrima fruit was isolated using column chromatography, and the antidiabetic properties of the anthocyanin were determined by the levels of α-amylase and α-glucosidase inhibition. Km and Vmax were also evaluated using the GraphPad Prism 7. The results of this study showed that the anthocyanin content of the fruit extract was 14.36 ± 0.33 mg/g, and following purification, this amount increased to 34.51 ± 0.42 mg/g. The highest of α-glucosidase inhibition was observed in the purified anthocyanin with IC50 = 0.71 ± 0.085 mg/ml, compared to acarbose as the baseline with IC50 = 8.8 ± 0.14 mg/ml, p < 0.0001. Purified anthocyanin of the mentioned fruit with IC50 = 1.14 ± 0.003 mg/ml had the greatest α-amylase inhibition, which was similar to acarbose as the standard with IC50 = 1 ± 0.085 mg/ml, p < 0.05. The inhibition of α-glucosidase and α-amylase by purified anthocyanin showed uncompetitive inhibition, and the enzyme inhibition by unpurified anthocyanin showed mixed inhibition. The obtained findings showed that Berberis integerrima fruit can be mentioned as a source of anthocyanin with antidiabetic properties.

This study focused on in silico investigation of SARS-CoV-2 Mpro inhibitors screened from 6663 quercetin similar compounds. Two promising compounds, blumeatin B (L1) and 3,5-dihydroxy-7,3',4',5'-tetramethoxyflavone (L2), were identified through machine learning based virtual screening and similarity analysis. They underwent molecular docking with Mpro and demonstrated strong interactions, with docking scores of -8.02 and -7.21kcal/mol, respectively. Various parameters (RMSD, RMSF, Rg, SASA, and the number of hydrogen bonds) observed during 200ns molecular dynamics (MD) simulation confirmed their stability. Principal component analysis (PCA) and dynamical cross-correlation matrix (DCCM) revealed minimal conformational changes and strongly correlated motions in the protein. End-state MM/GBSA free energy calculations for L1 and L2 with Mpro were -22.86 and -19.89kcal/mol. Density functional theory (DFT) studies at the B3LYP/6-311++G (d,p) level showed their polar nature, with electrophilicity index values exceeding 1.5eV. The HOMO-LUMO energy gaps of L1 and L2 were 4.04 and 3.57eV, aligning with the DOS spectra. Based on results from virtual screening, ADMET parameters, docking scores, hydrophobic interactions, hydrogen bonding, MD simulation, end-state free energy calculations, and DFT findings, L1 and L2 could be considered as promising SARS-CoV-2 Mpro inhibitors, requiring further experimental validation.

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4a–t and 12a–t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC50 = 15.85 µM) relative to reference drug acarbose (IC50 = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC50 = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein–ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management.

Diabetes mellitus is a major global health concern associated with severe metabolic and cardiovascular complications. This study evaluated the antidiabetic and antioxidant activities of Oxalis corniculata L. aerial parts, with a focus on α-glucosidase and α-amylase inhibition, using a combination of in vitro assays and in silico analyses. Among the tested fractions, the ethyl acetate fraction exhibited the strongest inhibitory activity against both enzymes, with IC50 values of 0.097 and 0.015 mg/mL for α-glucosidase and α-amylase, respectively, surpassing those of the reference drug, acarbose. This fraction also demonstrated potent antioxidant activity, with IC50 values of 0.025 and 0.020 mg/mL in DPPH and ABTS assays, respectively. To elucidate the underlying mechanisms beyond digestive enzyme inhibition, bioactive constituents were screened and evaluated using network pharmacology, molecular docking, molecular dynamics simulations, and density functional theory (DFT) calculations. Molecular docking and dynamic simulations confirmed stable and energetically favorable interactions with α-glucosidase and α-amylase. Network pharmacology analysis revealed that the antidiabetic effects of O. corniculata involve modulation of insulin resistance-related pathways, particularly PI3K/Akt signaling, GLUT4 translocation, and inflammation-associated targets, alongside regulation of oxidative stress through redox-related enzymes. Complementary DFT analysis provided molecular-level insights into the antioxidant mechanisms, highlighting favorable electronic properties that support efficient radical scavenging. Overall, this integrated experimental-computational study provided valuable evidence of O. corniculata aerial parts as a promising multi-target phytotherapeutic candidate for diabetes management, extending its therapeutic relevance beyond α-glucosidase and α-amylase inhibition.

Background Cholesterol biosynthesis is a critical pathway in cellular metabolism, with 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzing its committed step. HMGR inhibition has been widely explored as a therapeutic target for managing hypercholesterolemia, and statins are the most commonly used competitive inhibitors. However, the search for novel, natural HMGR inhibitors remains a vital area of research, due to the adverse effects associated with long-term statin use. Cochlospermum planchonii and Cochlospermum tinctorium are West African medicinal plants traditionally used to treat metabolic disorders, including dyslipidemia. Despite their usefulness, the specific bioactive compounds responsible for these effects are currently poorly characterized, justifying further investigations. Objective This study investigates the potential of phytochemicals from Cochlospermum planchonii and Cochlospermum tinctorium as natural inhibitors of human HMGR using molecular docking techniques. Methods A total of 84 phytochemicals from 2 species of Cochlospermum as reported in literature, were evaluated as potential inhibitors of HMGR. Using DataWarrior software, their drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties were screened in accordance with Lipinski’s Rule of Five. The 32 compounds that met the criteria were docked on PyRx against the HMG-binding site of HMGR, alongside atorvastatin (native ligand) and 6 known statins, which served as control ligands. Results Docking analysis of their two best binding modes showed that 10 (31.3%) out of the 32 screened phytochemicals demonstrated strong binding affinities and interactions with the HMG-binding pocket (residues 682‐694) of HMGR, with binding energy (ΔG) scores ranging from −4.6 to −6.0 kcal/mol, comparable to or exceeding those of statins (−4.6 to −5.7 kcal/mol). Their docking scores (−13.272 to −32.103) also compared favorably with those of statins (−25.939 to −36.584). Interestingly, 3-O-methylellagic acid (ID_13915428) demonstrated the strongest interaction, forming 26 binding interactions with the HMG-binding pocket residues, more than any compound, including statins. One-way ANOVA of the mean and SEM of the binding affinity scores for the phytochemicals and statins (9 replicates each) indicated a statistically significant difference at P&lt;.05 (total sample size n=153; actual P=.0001). Conclusions This study is the first to virtually screen and identify specific bioactive compounds isolated from Cochlospermum planchonii and Cochlospermum tinctorium with potential cholesterol-lowering effects in humans. The findings not only support the traditional use of these plants in West Africa to manage dyslipidemia and other ailments, but also present the phytochemicals as promising drug candidates for further optimization as natural inhibitors of HMGR. However, while this study provides valuable computational insights into the molecular interactions of the compounds with HMGR, further advanced computational, in vitro, and in vivo studies are still necessary to validate their inhibitory potential and therapeutic applications.

In humans, Epidermal Growth Factor Receptor (EGFR) is linked to small-cell lung cancer, breast cancer, and glioblastoma. Receptor kinase inhibitors against EGFR have become a standard treatment option for non-small cell lung cancer (NSCLC), breast cancer patients, and even for those with EGFR mutations or resistance. About 2734 FDA-approved medication compounds were subjected to virtual screening for EGFR kinase inhibitory activity. The top 30 molecules were chosen based on the binding affinity scores and subjected to extra-precision docking and binding free energy analysis. The ADMET profile of the top three hit molecules was verified to confirm their druggability nature. Top three hits- compound 1047 (ZINC000001550477), 1302 (ZINC00003781952), and 2332 (ZINC000019632618) were identified on account of their MMGBSA binding affinity values. The top three hit compounds were subjected to molecular dynamics (MD) simulation for 100 ns. The dynamic nature of the ligand-protein complex was analyzed which corroborated the results of molecular docking and MMGBSA analysis studies. All the top three hits were further subjected to steered MD studies for testing the strength of these ligand-receptor binding in the presence of an external force. Compound 2332 (ZINC000019632618) was identified as the best hit molecule that can be used as a lead to develop newer derivatives of EGFR kinase inhibitors. Communicated by Ramaswamy H. Sarma

The dengue virus (DENV) has four well-known serotypes, namely DENV1 to DENV4, which together cause 50-100 million infections worldwide each year. DENV NS2B/NS3pro is a protease recognized as a valid target for DENV antiviral drug discovery. However, NS2B/NS3pro conformational flexibility, involving in particular the NS2B region, is not yet completely understood and, hence, a big challenge for any virtual screening (VS) campaign. Molecular dynamics (MD) simulations were performed in this study to explore the DENV3 NS2B/NS3pro binding-site flexibility and obtain guidelines for further VS studies. MD simulations were done with and without the Bz-nKRR-H inhibitor, showing that the NS2B region stays close to the NS3pro core even in the ligand-free structure. Binding-site conformational states obtained from the simulations were clustered and further analysed using GRID/PCA, identifying four conformations of potential importance for VS studies. A virtual screening applied to a set of 31 peptide-based DENV NS2B/NS3pro inhibitors, taken from literature, illustrated that selective alternative pharmacophore models can be constructed based on conformations derived from MD simulations. For the first time, the NS2B/NS3pro binding-site flexibility was evaluated for all DENV serotypes using homology models followed by MD simulations. Interestingly, the number of NS2B/NS3pro conformational states differed depending on the serotype. Binding-site differences could be identified that may be crucial to subsequent VS studies.

DNA gyrase brings negative supercoils into DNA and loosens up certain positive supercoils that collect during replication and transcription and is a notable antibacterial target. To fight against the menace of antibiotic-resistant bacterial infections, we have employed various computational tools like high throughput virtual screening (HTVS), standard precision (SP) docking, extra precision (XP) docking, and molecular dynamics (MD) simulation studies to identify some potential DNA gyrase inhibitors. A focused library of 5968 anti-bacterial compounds was screened using the HTVS docking protocol of the glide module of Maestro. The top 200 docked compounds were further filtered using SP and XP docking protocols, and their free binding energies were calculated using MM-GBSA studies. The binding and stability of the top two compounds which showed better docking scores than the co-crystallized ligand (Clorobiocin) of DNA gyrase (PDB ID: 1KZN) were further probed by MD simulation of 100 ns using GROMACS. MD simulation study suggested that the compounds AM1 and AM5 form a stable complex with DNA gyrase with a good number of hydrogen bonds. XP docking study showed that interaction with the crucial amino acids for compounds AM1 and AM5 was like the co-crystallized ligand. These compounds were also predicted to be drug-like molecules with good water solubility and excellent absorption profiles. Based on the above studies, herein we report compounds AM1 (1R,3S)-1-(2-((3-(ammoniomethyl)phenyl)amino)-2-oxoethyl)-3-carbamoylpiperidin-1-ium and AM5 (1'S,2 s,4R)-4-ammonio-6-ethyl-1'-methylspiro[chromane-2,4'-piperidin]-1'-ium as potential DNA gyrase inhibitors which can be further developed as a potential lead against the menace of antibiotic resistance.

Lilium polyphyllum D. Don ex Royle (Liliaceae) bulbs are traditionally used to treat various ailments; however, their phytochemical composition and bioactivities remain rarely explored. This study aims to investigate the phytochemical composition, anticancer, antidiabetic, and antioxidant activities of L. polyphyllum bulb extract and fractions to validate its traditional use and explore new therapeutic applications. Gas chromatography-mass spectrometry analysis was used for phytochemical characterization, while in silico toxicity predictions of the major compounds were carried out using online tools Swiss ADME and ProTox-3.0. Anticancer activity was performed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, whereas antidiabetic potential was examined via α-glucosidase and α-amylase enzyme inhibition assays. Antioxidant capacity was determined using 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid radical scavenging methods. Phytochemical analysis of hydromethanolic extract (Cr. MeOH-Ext) and hexane fraction (n-Hex-fr) identified 37 compounds, including methyl esters of eicosanoic, hexadecanoic, linoleic, and linolenic acid. In silico studies predicted drug-like and non-toxic properties of the major identified compounds. In the MTT assay, the chloroform fraction (Chl-fr) (half-maximal inhibitory concentration [IC50] = 2.85 ± 0.16µM) and n-Hex-fr (IC50 = 6.41 ± 0.20µM) demonstrated potent cytotoxicity against HL-60 leukemia cells, comparable to venetoclax (IC50 = 6.26 ± 0.41µM). Flow cytometry analysis showed that the cytotoxic effect was probably due to apoptosis. In α-glucosidase inhibition, the Cr. MeOH-Ext (86.18%) and aqueous fraction (Aq-fr) (84.09%) showed good activity, with IC50 values of 203.30 and 143.00µg/mL, respectively. In α-amylase inhibition, the Aq-fr (79.56%) and Cr. MeOH-Ext (77.77%) was found most active. Likewise, the Aq-fr and Cr. MeOH-Ext exhibited good radical scavenging effects. Our findings indicate that L. polyphyllum bulbs possess promising anticancer and antidiabetic properties due to their distinct phytochemical composition.

Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.