Binding Interaction Patterns Research Articles

Drug repurposing for diabetes mellitus: In silico and in vitro investigation of DrugBank database for α-glucosidase inhibitors

The process of developing novel compounds/drugs is arduous, time-intensive, and financially burdensome, characterized by a notably low success rate and relatively high attrition rates. To alleviate these challenges, compound/drug repositioning strategies are employed to predict potential therapeutic effects for DrugBank-approved compounds across various diseases. In this study, we devised a computational and enzyme inhibitory mechanistic approach to identify promising compounds from the pool of DrugBank-approved substances targeting Diabetes Mellitus (DM). Molecular docking analyses were employed to validate the binding interaction patterns and conformations of the screened compounds within the active site of α-glucosidase. Notably, Asp352 and Glu277 participated in interactions within the α-glucosidase-ligand complexes, mediated by conventional hydrogen bonding and van der Waals forces, respectively. The stability of the docked complexes (α-glucosidase-compounds) was scrutinized through Molecular Dynamics (MD) simulations. Subsequent in vitro analyses assessed the therapeutic potential of the repositioned compounds against α-glucosidase. Kinetic studies revealed that “Forodesine” exhibited a lower IC50 (0.24 ± 0.04 mM) compared to the control, and its inhibitory pattern corresponds to that of competitive inhibitors. In-depth in silico secondary structure content analysis detailed the interactions between Forodesine and α-glucosidase, unveiling significant alterations in enzyme conformation upon binding, impacting its catalytic activity. Overall, our findings underscore the potential of Forodesine as a promising candidate for DM treatment through α-glucosidase inhibition. Further validation through in vitro and in vivo studies is imperative to confirm the therapeutic benefits of Forodesine in conformational diseases such as DM.

In vivo determination of analgesic and anti-inflammatory activities of isolated compounds from Cleome amblyocarpa and molecular modelling for the top active investigated compounds.

Cleome amblyocarpa Barr. and Murb. from the family Cleomaceae is used in folk medicine as it has analgesic, anti-inflammatory, antibacterial and antioxidant activities. In this study, ten compounds from the whole plant of C. amblyocarpa, a wild plant that grows in the Sinai Peninsula of Egypt, were isolated. Six compounds, β-sitosterol 3-O-β-d-glucoside 2, calycopterin 5, rhamnocitrin 6, 17α-hydroxycabraleahy-droxylactone 7, cleogynol 8, and β-sitosterol 10 were first isolated from this species. In addition, four previously reported compounds, kaempferol-3, 7-dirhamnoside 1, 15α-acetoxycleomblynol A 3, and 11-α-acetylbrachy-carpone-22(23)-ene 4, as well as cleocarpanol 9, were isolated and identified. Isolated compounds were evaluated to determine their analgesic properties utilizing a hot-plate test method, and their anti-inflammatory effects utilizing rat paw edema. In a hot-plate test, compounds 3, 4, 7, 8, and 9 showed significant pain inhibition in latency time as compared to the normal group. Compounds 3-9 exhibited a significant inhibition of carrageenan-induced inflammation. According to the results of this work, compounds 3 and 4 (Dammarane triterpenoid) have the strongest analgesic/anti-inflammatory activity as compared to the other tested compounds. These results give support to the medicinal benefits of the plant as an analgesic along with an anti-inflammatory agent in traditional therapy. Molecular modelling studies of the isolated compounds 3 and 4 assessed the molecular affinity and binding interaction patterns for these compounds towards COX-2 as compared to specific COX-2 inhibitors and in relation to COX-1 isozyme. Compound 3 revealed extended accommodation across COX-2's hydrophobic sub-pockets and preferential thermodynamic stability across molecular dynamics simulations.

Design, synthesis of novel chromene-based scaffolds targeting hepatocellular carcinoma: Cell cycle arrest, cytotoxic effect against resistant cancer cells, apoptosis induction, and c-Src inhibition.

New chromene derivatives were synthesized based on 4-(3,4-dimethoxy)-4H-chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40-141.22 μM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c-Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c-Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI-38 cells was confirmed via its IC50 of 115.75 μM comparable with 5-FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5-FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29-fold increase in the total number of apoptotic cells indicating pre-G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase-3, caspase-7, caspase-9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c-Src kinase enzyme active site.

Design, Synthesis, Characterization and Biological Activities of Novel S‐(Acyloxy)butyl‐N,N‐Diethyldithiocarbamate Compounds

AbstractIn this study, S‐(Acyloxy)butyl‐N,N‐Diethyldithiocarbamate compounds (P1‐P7) were synthesized by s‐alkylation of N,N‐diethyldithiocarbamate sodium trihydrate with 4‐chlorobutylcarboxylates. P1–P7 were characterized by full infrared, NMR spectroscopy and elemental analyses. Additionally, the impacts of these compounds were investigated on some metabolic enzymes and then compared to the reference compounds. It was observed that the DEDTCA esters generally had lower IC50 and Ki values. Among them, P4 and P6 molecules had lower IC50 with 112.47 and 111.55 μM; and Ki values: 105.53±7.17 and 102.06±5.08 μM against AChE, respectively. Furthermore, molecular docking simulations approved the binding interaction patterns and structural orientations of N,N‐diethyldithiocarbamic acid derivatives within the binding sites of AChE, BChE and α‐glucosidase. Taken together, the compound P6 performs strong distant bond interactions against tacrine for AChE and BChE enzymes within the scope of in silico study. The compound P4, on the other hand, exhibits good interactions with the target by making hydrophobic, pi‐sulfur and pi‐sigma bonds as well as hydrogen bonds compared to acarbose as standard compound against α‐glucosidase. These can be further analyzed as potent candidate compounds in biological studies of the respective enzymes.

Thioether-substituted Benzimidazolium Salts: Synthesis, Characterization, Crystal Structure, and Their Inhibitory Properties Against Acetylcholinesterase and Xanthine Oxidase

The sulfurous compounds are known as organosulfur, which has been associated with numerous biological activities in both natural products and synthetic organic compounds. In this work, we present the synthesis of a series of 4-(methylthio)benzyl substituted benzimidazolium salts. All compounds were characterized using NMR (1H and 13C) and FTIR spectroscopic methods as well as an elemental analysis technique. The molecular and crystal structures of the compound 1a were determined by X-ray crystallography revealing that the compound crystallized in the trigonal space group R-3. Enzyme inhibition studies demonstrated that a new series of sulfurous compounds precursors were highly potent inhibitors for xanthine oxidase (XO) and acetylcholinesterase (AChE) enzyme. The IC50 values were found in the range of 0.548 ± 0.033 to 0.725 ± 0.043 µM for XO promising strategy for the treatment from gout disease, while IC50 values were found in the range 0.813 ± 0.076 to 1.149 ± 0.072 µM toward AChE as the key enzyme promising strategy for the treatment of neurological disorders such as Alzheimer's disease (AD). Furthermore, pharmacodynamics studies prove the binding interaction patterns, structural orientations and drug potential of sulfide derivatives in the binding sites of xanthine oxidase (XO) and acetylcholinesterase (AChE) enzymes. Potential inhibitors (compounds 1d-f) were compared with standard compounds allopurinol (for XO) and donepezil (for AChE). Compared to the positive compound of target XO, the 4-vinylbenzyl group of potential compound 1f and the 4-methylbenzyl group of compound le more effectively formed electrostatic and hydrophobic interactions with the target's interaction site. While donepezil as standard compound interacts only at the peripheral anionic site of AChE, the related compounds interact with both regions (PAS and CAS sites) of the same target. These compounds were placed at the active sites of the respective targets by molecular docking method using AutoDock software. Binding energy, binding modes and interaction types were used to evaluate the series of 4-(methylthio)benzyl substituted benzimidazolium salts's ability to bind to each target. Binding energy lower than zero remarks spontaneous binding, and equal and/or lower than -5 kcal/mol remarks good binding. Besides XO, the related compounds show higher activity against the AChE enzyme. They can also be analyzed as strong candidate compounds in biological studies of related enzymes.

Strontium-doped chromium oxide for RhB reduction and antibacterial activity with evidence of molecular docking analysis.

The emergence of multi-drug resistance (MDR) in aquatic pathogens and the presence of cationic dyes are the leading causes of water contamination on a global scale. In this context, nanotechnology holds immense promise for utilizing various nanomaterials with catalytic and antibacterial properties. This study aimed to evaluate the catalytic and bactericidal potential of undoped and Sr-doped Cr2O3 nanostructures (NSs) synthesized through the co-precipitation method. In addition, the morphological, optical, and structural properties of the resultant NSs were also examined. The optical bandgap energy of Cr2O3 has been substantially reduced by Sr doping, as confirmed through extracted values from absorption spectra recorded by UV-Vis studies. The field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) micrographs illustrate that the composition of Cr2O3 primarily consisted of agglomerated, irregularly shaped NSs with a morphology resembling nanoflakes. Moreover, the presence of Sr in the lattice of Cr2O3 increased the roughness of the resulting NSs. The catalytic activity of synthesized NSs was analyzed by their reduction ability of Rhodamine B (RhB) dye in the dark under different pH conditions. Their antibacterial activity was evaluated against MDR Escherichia coli (E. coli). Sr doping increased antibacterial efficiency against MDR E. coli, as indicated by inhibition zone measurements of 10.15 and 11.75mm at low and high doses, respectively. Furthermore, a molecular docking analysis was conducted to determine the binding interaction pattern between NSs and active sites in the target cell protein. The findings corroborated antimicrobial test results indicating that Sr-Cr2O3 is the most effective inhibitor of FabH and DHFR enzymes.

An Analysis of the Structural Relationship between Thyroid Hormone-Signaling Disruption and Polybrominated Diphenyl Ethers: Potential Implications for Male Infertility

Polybrominated diphenyl ethers (PBDEs) are a common class of anthropogenic organobromine chemicals with fire-retardant properties and are extensively used in consumer products, such as electrical and electronic equipment, furniture, textiles, and foams. Due to their extensive use, PBDEs have wide eco-chemical dissemination and tend to bioaccumulate in wildlife and humans with many potential adverse health effects in humans, such as neurodevelopmental deficits, cancer, thyroid hormone disruption, dysfunction of reproductive system, and infertility. Many PBDEs have been listed as chemicals of international concern under the Stockholm Convention on Persistent Organic Pollutants. In this study, the aim was to investigate the structural interactions of PBDEs against thyroid hormone receptor (TRα) with potential implications in reproductive function. Structural binding of four PBDEs, i.e., BDE-28, BDE-100, BDE-153 and BDE-154 was investigated against the ligand binding pocket of TRα using Schrodinger's induced fit docking, followed by molecular interaction analysis and the binding energy estimation. The results indicated the stable and tight binding of all four PDBE ligands and similarity in the binding interaction pattern to that of TRα native ligand, triiodothyronine (T3). The estimated binding energy value for BDE-153 was the highest among four PBDEs and was more than that of T3. This was followed by BDE-154, which is approximately the same as that of TRα native ligand, T3. Furthermore, the value estimated for BDE-28 was the lowest; however, the binding energy value for BDE-100 was more than BDE-28 and close to that of TRα native ligand, T3. In conclusion, the results of our study suggested the thyroid signaling disruption potential of indicated ligands according to their binding energy order, which can possibly lead to disruption of reproductive function and infertility.

Computational prognostic evaluation of Alzheimer's drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches.

Novel drug design is time consuming and very expensive process having particularly low success rate. To overcome these difficulties, drug repositioning also referred to as drug repurposing approach is being used to predict the possible alternative therapeutic effects of drugs approved by FDA for different diseases. In this study, we designed a computational mechanism-based approach to fetch promising drugs from the pool of FDA approved drugs to screen them for treatment of Alzheimer's disease (AD). The binding interaction patterns and conformations of screened drugs within active region of MAP Kinase Activating Death Domain (MADD) protein were confirmed through molecular docking profiles. The possible associations of selected drugs with AD related genes were predicted by pharmacogenomics analysis and confirmed through data mining. Furthermore, the stability behavior of docked (Drug-MADD) complexes was checked by MD simulations. Taken together, five drugs displayed promising features and can be used as possible therapeutic agents in the treatment of AD after detailed in vitro studies and clinical assessments.

Exploration of Flavonoids as Lead Compounds against Ewing Sarcoma through Molecular Docking, Pharmacogenomics Analysis, and Molecular Dynamics Simulations.

Ewing sarcoma (ES) is a highly malignant carcinoma prevalent in children and most frequent in the second decade of life. It mostly occurs due to t(11;22) (q24;q12) translocation. This translocation encodes the oncogenic fusion protein EWS/FLI (Friend leukemia integration 1 transcription factor), which acts as an aberrant transcription factor to deregulate target genes essential for cancer. Traditionally, flavonoids from plants have been investigated against viral and cancerous diseases and have shown some promising results to combat these disorders. In the current study, representative flavonoid compounds from various subclasses are selected and used to disrupt the RNA-binding motif of EWS, which is required for EWS/FLI fusion. By blocking the RNA-binding motif of EWS, it might be possible to combat ES. Therefore, molecular docking experiments validated the binding interaction patterns and structural behaviors of screened flavonoid compounds within the active region of the Ewing sarcoma protein (EWS). Furthermore, pharmacogenomics analysis was used to investigate potential drug interactions with Ewing sarcoma-associated genes. Finally, molecular dynamics simulations were used to investigate the stability of the best selected docked complexes. Taken together, daidzein, kaempferol, and genistein exhibited a result comparable to ifosfamide in the proposed in silico study and can be further analyzed as possible candidate compounds in biological in vitro studies against ES.

Structural Dynamics of P‐Rex1 Complexed with Natural Leads Establishes the Protein as an Attractive Target for Therapeutics to Suppress Cancer Metastasis

Phosphatidylinositol 3,4,5‐trisphosphate‐ (PIP3‐) dependent Rac exchanger 1 (P‐Rex1) functions as Rho guanine nucleotide exchange factor and is activated by synergistic activity of Gβγ and PIP3 of the heterotrimeric G protein. P‐Rex1 activates Rac GTPases for regulating cell invasion and migration and promotes metastasis in several human cancers including breast, prostate, and skin cancer. The protein is a promising therapeutic target because of its multifunction roles in human cancers. Herein, the present study attempts to identify selective P‐Rex1 natural inhibitors by targeting PIP3‐binding pocket using large‐size multiple natural molecule libraries. Each library was filtered subsequently in FAF‐Drugs4 based on Lipinski’s rule of five (RO5), toxicity, and filter pan assay interference compounds (PAINS). The output hits were virtually screened at the PIP3‐binding pocket through PyRx AutoDock Vina and cross‐checked by GOLD. The best binders at the PIP3‐binding pocket were prioritized using a comparative analysis of the docking scores. Top‐ranked two compounds with high GOLD fitness score (>80) and lowest AutoDock binding energy (< ‐12.7 kcal/mol) were complexed and deciphered for molecular dynamics along with control‐P‐Rex1 complex to validate compound binding conformation and disclosed binding interaction pattern. Both the systems were seen in good equilibrium, and along the simulation time, the compounds are in strong contact with the P‐Rex1 PIP3‐binding site. Hydrogen bonding analysis towards simulation end identified the formation of 16 and 22 short‐ and long‐distance hydrogen bonds with different percent of occupancy to the PIP3 residues for compound I and compound 2, respectively. Radial distribution function (RDF) analysis of the key hydrogen bonds between the compound and the PIP3 residues demonstrated a strong affinity of the compounds to the mentioned PIP3 pocket. Additionally, MMGB/PBSA energies were performed that confirmed the dominance of Van der Waals energy in complex formation along with favorable contribution from hydrogen bonding. These findings were also cross‐validated by a more robust WaterSwap binding energy predictor, and the results are in good agreement with a strong binding affinity of the compounds for the protein. Lastly, the key contribution of residues in interaction with the compounds was understood by binding free energy decomposition and alanine scanning methods. In short, the results of this study suggest that P‐Rex1 is a good druggable target to suppress cancer metastasis; therefore, the screened druglike molecules of this study need in vitro and in vivo anti‐P‐Rex1 validation and may serve as potent leads to fight cancer.

Comparative sequence analysis of SARS nCoV and SARS CoV genomes for variation in structural proteins

SARS-nCoV was identified as corona virus had spread worldwide very quickly and affected more than million people worldwide. To halt this acceleration and for efficient control the knowledge on genomic information is of utmost importance. We attempted to determine the nature of variation i.e., insertion, deletion, substitution, among structural sequences required to code for membrane, spike, nucleocapsid, envelope protein and glycosylation variation between SARS CoV and SARS nCoV spike glycoproteins, respectively. Comparative sequence analysis was performed by using retrieved sequences from the NCBI database. The analyzed sequences revealed, that the sequences coding for envelope protein show minor substituting amino acids. SARS CoV showed 94.74 percent amino acid identities with SARS nCoV amino acid sequences coding for envelope protein. In comparison to SARS nCoV, distinct amino acid residues vary in SARS CoV sequences coding for membrane, nucleocapsid, and spike proteins, respectively. S protein coding sequences of SARS CoV exhibited one deletion, six insertion and six hundred three substitutions in SARS nCoV sequence. Insertion of valine was found in receptor binding domain of SARS nCoV at position 487, and NSPR amino acid residues at position 683–686. Deletions and substitutions were also found in nucleotide sequences of strain B.1.617.2 of SARS nCoV. Additionally, binding interaction pattern of ACE2 receptor protein with original wild-type SARS-CoV-2 strain with the recently evolved Omicron variant was also evaluated. The docking results substantiated that the specific variation in binding residues is likely to impact virulence pattern of both variants.

Molecular Modeling and Docking Studies of 2,4,5-Trisubstituted Pyrimidines as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q 2 = 0.828, r 2 = 0.988, r 2 pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r 2 = 0.968, r 2 pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs.

Z. officinale-doped silver/calcium oxide nanocomposites: Catalytic activity and antimicrobial potential with molecular docking analysis

In this study, green synthesized Ag/CaO combined with a reducing agent based on a plant extract was synthesized. Then, the catalytic and antimicrobial potential of extract doped-Ag/CaO was investigated. Bio-reducing synthesis protocol was followed to fabricate Ag/CaO nanocomposites (NCs) by reducing and capping with Zingiber officinale. A series of characterization techniques was employed to examine structural, morphological and optical properties of Ag/CaO. The experimental findings favored doped nanocomposites for use as effective catalysts that degraded toxic dyes such as methylene blue and ciprofloxacin and exhibited strong antimicrobial activity against Escherichia coli (E. coli), and Staphylococcus aureus (S. aueus). Furthermore, a molecular docking investigation determined binding interaction patterns between NCs and targeted cell protein active sites. The obtained results suggested green synthesized Ag/CaO as the most effective inhibitor of dihydrofolate reductase, DNA gyrase, and FabB enzymes. Findings revealed highly economical, non-toxic, and readily available Z. officinale rhizome extract as a potential capping agent to fabricate Ag/CaO for potential applications to reduce major economic losses in the dairy industry for the first time in Pakistan.

Deciphering the Active Compounds and Mechanisms of HSBDF for Treating ALI via Integrating Chemical Bioinformatics Analysis.

The Huashi Baidu Formula (HSBDF), a key Chinese medical drug, has a remarkable clinical efficacy in treating acute lung injury (ALI), and it has been officially approved by the National Medical Products Administration of China for drug clinical trials. Nevertheless, the regulated mechanisms of HSBDF and its active compounds in plasma against ALI were rarely studied. Based on these considerations, the key anti-inflammatory compounds of HSBDF were screened by molecular docking and binding free energy. The key compounds were further identified in plasma by LC/MS. Network pharmacology was employed to identify the potential regulatory mechanism of the key compounds in plasma. Next, the network pharmacological prediction was validated by a series of experimental assays, including CCK-8, EdU staining, test of TNF-α, IL-6, MDA, and T-SOD, and flow cytometry, to identify active compounds. Molecular dynamic simulation and binding interaction patterns were used to evaluate the stability and affinity between active compounds and target. Finally, the active compounds were subjected to predict pharmacokinetic properties. Molecular docking revealed that HSBDF had potential effects of inhibiting inflammation by acting on IL-6R and TNF-α. Piceatannol, emodin, aloe-emodin, rhein, physcion, luteolin, and quercetin were key compounds that may ameliorate ALI, and among which, there were five compounds (emodin, aloe-emodin, rhein, luteolin, and quercetin) in plasma. Network pharmacology results suggested that five key compounds in plasma likely inhibited ALI by regulating inflammation and oxidative damage. Test performed in vitro suggested that HSBDF (0.03125 mg/ml), quercetin (1.5625 μM), emodin (3.125 μM), and rhein (1.5625 μM) have anti-inflammatory function against oxidative damage and decrease apoptosis in an inflammatory environment by LPS-stimulation. In addition, active compounds (quercetin, emodin, and rhein) had good development prospects, fine affinity, and stable conformations with the target protein. In summary, this study suggested that HSBDF and its key active components in plasma (quercetin, emodin, and rhein) can decrease levels of pro-inflammatory factors (IL-6 and TNF-α), decrease expression of MDA, increase expression of T-SOD, and decrease cell apoptosis in an inflammatory environment. These data suggest that HSBDF has significant effect on anti-inflammation and anti-oxidative stress and also can decrease cell apoptosis in treating ALI. These findings provided an important strategy for developing new agents and facilitated clinical use of HSBDF against ALI.

Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies.

Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.

Elastase inhibitory activity of quinoline Analogues: Synthesis, kinetic mechanism, cytotoxicity, chemoinformatics and molecular docking studies

Herein, we have synthesized quinoline united various Schiff base derivatives (Q1-Q13) and systematically characterized them using diverse analytical practices such as 1H NMR, 13C NMR, FT-IR and LC-MS respectively. All of the target compounds that have been synthesized were tested for elastase inhibition, and the findings were compared to the standard drug oleanolic acid. Among the entire series, compound Q11 (IC50 = 0.897 ± 0.015 µM) exhibit most promising elastase inhibitory activity than oleanolic acid (Standard) having an IC50 value of 13.426 ± 0.015 µM. Also, the utmost effectivecompound Q11 was used for kinetic mechanism investigation based on in-vitro data, from which it has been concluded that compound Q11 inhibits elastase competitively. Furthermore, utilizing the MTT test approach, the most effective compounds were assessed for cytotoxicity on B16F10 melanoma cells. From the cytotoxicity experiment, the most potent compound did not display any hazardous response against B16F10 melanoma cells despite being treated at high concentrations. Additionally, the molecular docking study was settled to govern the binding interaction pattern among an enzyme and inhibitors.

Synthesis, carbonic anhydrase inhibition, anticancer activity, and molecular docking studies of 1,3,4-oxadiazole derivatives.

In this work, we have synthesized various organic compounds possessing 1,3,4-oxadiazole as a core structure and the structure of the newly synthesized target compounds has been revealed using different analytical approaches such as FT-IR, LCMS, and NMR (proton and carbon), respectively. The in vitro carbonic anhydrase potentials of these synthesized 17 different analogues were investigated. The result suggests that compound 7g, a 3-pyridine substituted analogue with an IC50 of 0.1µM, was found to have the most potent carbonic inhibitory activity (11-fold more active) than the positive control (acetazolamide) with an IC50 of 1.1 ± 0.1µM. Besides, among the series 7(a-q) approved in the identification of four potent carbonic anhydrase inhibitors with the IC50 standards varies from 0.1 to 1.0 ± 0.1µM. Additionally, the non-competitive behaviour for potent compound 7g was analysed using the Lineweaver-Burk plot from the kinetic study. Furthermore, the anticancer activity of all the synthesized compounds screened against B16F10 melanoma cells using the MTT assay method. Additionally, the molecular docking studies revealed that 7g inhibitor shows good binding energy as well as good binding interaction pattern along with enzyme.

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

Interaction of a hydrophilic molecule with bovine serum albumin: A combined multi-spectroscopic, microscopic and isothermal calorimetric study in the presence of graphene oxide

One of the most widely studied plasma protein is bovine serum albumin (BSA), and it plays a crucial role in the binding and transportation of many exogenous and endogenous drugs. Coumarin derivatives play a crucial role as an analgesic, anticancer, and anticoagulant agent. Here in this report, we have studied the binding interaction between a 7-amino coumarin derivative, namely 7-(N, N′-diethylamino)coumarin-3-carboxylic acid (7-DCCA) with BSA and also have found out the effect of graphene oxide (GO) on the binding interaction. The binding interaction was probed by employing various spectroscopic, microscopic, isothermal titration calorimetric (ITC), and by using molecular docking studies. The change in absorption and emission maxima position of BSA and 7-DCCA in the absence and presence of GO along with the change in absorbance and emission intensity when we titrated by 7-DCCA or BSA respectively indicates the strong complexation between 7-DCCA and BSA. From the fluorescence resonance energy transfer study, the average distance between tryptophan 213 of the BSA (donor), and the 7-DCCA (acceptor) is found ~50 Ǻ. From excited-state lifetime and fluorescence lifetime imaging (FLIM) studies, we observed that the average lifetime of 7-DCCA is much higher in the presence of BSA compared to buffer medium and in the presence of BSA a heterogeneous environment was created around 7-DCCA. Again in the presence of GO, the formation of a complex of 7-DCCA with a low concentration of BSA shows greater binding interaction as compared to that in the absence of GO. Time-resolved fluorescence anisotropy measurement shows that the addition of GO provides a restricted environment surrounding the 7-DCCA molecule in the presence of both low and high concentrations of BSA. CD study demonstrates the same extent of reduction of α-helical content of BSA protein on binding with 7-DCCA in the absence and presence of GO. ITC study revealed that the interaction between 7-DCCA and BSA is favoured by negative enthalpy change and positive entropy change. Also, from the ITC study, we find out that GO doesn't inflict significant change in the overall global binding interaction pattern, rather it inflicts changes in the mechanistic pathways of binding between 7-DCCA and BSA. Step-scan FTIR studies show the modification of amide I and amide II bonds with time when complexation occurs between BSA and 7-DCCA in the absence and presence of GO. The docking result reveals that the deprotonated form of 7-DCCA has positioned at a distance of ~3.7 nm from Trp 213. Thus these interactions play a central role in the development of coumarin derivative based small molecules to be used for both academic and industrial purposes.

Three new acrylic acid derivatives from Achillea mellifolium as potential thymidine phosphorylase inhibitor: molecular docking and MD simulation studies

Discovery of potent inhibitors of thymidine phosphorylase (TP) can offer appropriate approach in cancer treatment owing to it’s over expression in various human tumors compared to normal healthy tissues. Thymidine phosphorylase alongside 2-deoxy-D-ribose are reported as promoters of unwanted angiogenesis in cancerous cells. In this study, three new acrylic acid derivatives (1–3) have been isolated from ethyl acetate fraction of Achillea mellifolium. The characterization of these compounds (1–3) was done using UV, IR, 1 D and 2 D-NMR spectroscopy (1H-NMR, 13C-NMR, HMBC, NOESY) and mass spectrometry. The structure of these acrylic acid derivatives were ethyl (E)-3-((1S,5R)-5-methoxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)acrylate (1), methyl (E)-3-((1S,5R)-5-methoxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)acrylate (2) and (4S,6R)-6-methoxy-3,5,5-trimethyl-4-((E)-3-oxobut-1-en-1-yl)cyclohex-2-en-1-one (3). Thymidine phosphorylase (TP) inhibition studies showed compound 3 as most active inhibitor of TP with IC50 value 57.81 ± 3.41 while compound 1 and 2 showed IC50 value as 158.9 ± 0.97 and 89.92 ± 0.37, respectively. In addition, molecular docking studies of compound (1–3) were performed to shed light on their binding interaction patterns for binding into active pocket of TP. Similarly, all compounds (1–3) were evaluated for their anti-oxidant potential showing anti-oxidant activities with IC50 value ranging from 49.73 ± 0.41 to 79.81 ± 0.39. Later, these compound-protein (1–3) complexes were further subjected to MD simulations studies (50 ns) involving root mean square deviation, root mean square fluctuation, and secondary structure analysis to explore their binding mode stability inside active pocket. Communicated by Ramaswamy H. Sarma