A spectroscopic, thermodynamic and molecular docking study of the binding mechanism of dapoxetine with calf thymus DNA

Dapoxetine is a selective serotonin reuptake inhibitor, used to treat premature ejaculation in men. Dapoxetine may interact with theDNAand hence this study investigated dapoxetine and calf thymusDNA(ctDNA) binding interaction. The interaction study of ligands to DNA is of importance in the development of molecular probes and therapeutic agents. Spectroscopic techniques including spectrofluorometry and spectrophotometry were employed to study this interaction. Fluorescence studies indicated a static quenching mechanism between dapoxetine and ctDNA. Groove binding was suggested as the mode of interaction between dapoxetine and ctDNA based onUVabsorption, circular dichroism (CD) spectroscopy, iodide quenching and molecular docking studies. The studies conducted at three different temperatures 298, 303 and 310 K indicated a strong binding interaction at higher temperatures. Thermodynamic studies conducted indicated involvement of hydrophobic interaction between ctDNA and dapoxetine and were entropy-driven. Ethidium bromide probe study suggested that dapoxetine does not bind to ctDNA in an intercalative fashion. Iodide quenching studies further proved the non-intercalative binding of ctDNA with dapoxetine. Ionic strength studies conducted ruled out the electrostatic binding mechanism between ctDNA and dapoxetine. Molecular docking analysis performed for the dapoxetine with calf thymus DNA (ctDNA) interaction and confirmed minor groove binding of dapoxetine to ctDNA. The study helped to reveal the binding interaction mechanism between dapoxetine and ctDNA

Design, Synthesis, and Biological Evaluation of 2-Mercaptobenzoxazole Derivatives as Potential Multi-Kinase Inhibitors

A series of 12 compounds was designed and synthesized, based on 2-mercaptobenzoxazole derivatives containing either the substituted benzenes 4a–d, substituted isatins 5a–f, or heterocycles 6a–b. The in vitro antiproliferative activity of the compounds was evaluated against hepatocellular carcinoma (HepG2), mammary gland cancer (MCF-7), breast cancer (MDA-MB-231), and the epithelioid cervix carcinoma (HeLa) cancer cell lines. Compounds 4b, 4d, 5d, and 6b had the most potent antiproliferative activity, with IC50 values ranging from 2.14 to 19.34 µM, compared to the reference drugs, doxorubicin and sunitinib. Compound 6b revealed a remarkably broad antitumor activity pattern against HepG2 (IC50 6.83 µM), MCF-7 (IC50 3.64 µM), MDA-MB-231 (IC50 2.14 µM), and HeLa (IC50 5.18 µM). In addition, compound 6b showed potent inhibitory activities against EGFR, HER2, VEGFR2, and the CDK2 protein kinase enzymes, with IC50 values of 0.279, 0.224, 0.565, and 0.886 µM, respectively. Moreover, compound 6b induced caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Finally, a molecular docking simulation was performed for compound 6b to predict the potential ligand–protein interactions with the active sites of the EGFR, HER2, and VEGFR2 proteins

A Comprehensive Investigation of Interactions between Antipsychotic Drug Quetiapine and Human Serum Albumin Using Multi-Spectroscopic, Biochemical, and Molecular Modeling Approaches

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy

Design, synthesis, antitumor evaluation, and molecular docking of novel pyrrolo[2,3-d]pyrimidine as multi-kinase inhibitors

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis

Mechanistic interaction study of 5,6-Dichloro-2-[2-(pyridin-2-yl)ethyl]isoindoline-1,3-dione with bovine serum albumin by spectroscopic and molecular docking approaches

A synthesized and promising biologically hypoglycemic compound 5,6-Dichloro-2-[2-(pyridin-2-yl)ethyl]isoindoline-1,3-dione (5e) was studied for its binding to a model protein (bovine serum albumin; BSA) by spectroscopic and molecular simulation approaches. Fluorescence studies revealed that 5e quenched BSA’s intrinsic fluorescence by static quenching. The experiments were performed at three different temperatures and the quenching constants and binding constants were evaluated. Stern-Volmer constant (Ksv) values decreased from 1.36 × 104 to 1.20 × 104 as the temperature increased suggesting static quenching involvement in the interaction. Decreased binding constants from 1.70 × 104 to 4.57 × 103 at higher temperatures indicated instability of the complex at rising temperatures. Site I (subdomain IIA) of BSA was found to interact with 5e. The thermodynamic results showed the binding interaction was spontaneous and enthalpy driven. The secondary structure alterations in BSA due to interaction with 5e were studied by UV–visible, synchronous fluorescence, and three-dimensional fluorescence spectra. The results indicate the 5e binds effectively to the BSA and thus, this study can be useful in further exploring the pharmacokinetics and pharmacodynamics of 5e. Keywords: BSA, Thermodynamics, Docking, Fluorescence quenching, Spectroscop

Synthesis of Novel Diclofenac Hydrazones: Molecular Docking, Anti-Inflammatory, Analgesic, and Ulcerogenic Activity

This study was aimed to design novel diclofenac hydrazones having anti-inflammatory and analgesic activity with gastric sparing effect. A new series of 2-[2-(2,6-dichloroanilino)phenyl]-N’-[(substituted phenyl) methylidene] acetohydrazide derivatives (1−14) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activity. The compounds were identified and confirmed by elemental analysis and spectral data. During anti-inflammatory activity by carrageenan-induced paw edema method, compounds (2, 3, 7, 8, 11, and 13) were found to be most promising. Compounds 3, 8, and 13 have been found to have significant analgesic activity compared to the reference drug diclofenac in analgesic activity by both the hot plate method and acetic acid-induced writhing method. The compounds which presented highly significant anti-inflammatory and analgesic activity were further tested for their ulcerogenic activity. Compounds 3 and 8 showed maximum ulcerogenic reduction activities. Compound 8 was found to have LD50 of 168 mg/kg. Compound 8 with 3,5-dimethoxy-4-hydroxyphenyl substitution was found to be the most promising anti-inflammatory and analgesic agent with gastric sparing activity. Molecular docking of compounds was performed for COX−1/COX−2 binding site. Lead compound 8 showed better binding affinities of −9.4 kJ/mol with both COX-1 and COX-2 as compared to the standard drug, diclofenac with binding affinities of −6.6 kJ/mol and −8.1 kJ/mol for COX−1 and COX−2, respectively

Interaction Characterization of a Tyrosine Kinase Inhibitor Erlotinib with a Model Transport Protein in the Presence of Quercetin: A Drug–Protein and Drug–Drug Interaction Investigation Using Multi-Spectroscopic and Computational Approaches

The interaction between erlotinib (ERL) and bovine serum albumin (BSA) was studied in the presence of quercetin (QUR), a flavonoid with antioxidant properties. Ligands bind to the transport protein BSA resulting in competition between different ligands and displacing a bound ligand, resulting in higher plasma concentrations. Therefore, various spectroscopic experiments were conducted in addition to in silico studies to evaluate the interaction behavior of the BSA-ERL system in the presence and absence of QUR. The quenching curve and binding constants values suggest competition between QUR and ERL to bind to BSA. The binding constant for the BSA-ERL system decreased from 2.07 × 104 to 0.02 × 102 in the presence of QUR. The interaction of ERL with BSA at Site II is ruled out based on the site marker studies. The suggested Site on BSA for interaction with ERL is Site I. Stability of the BSA-ERL system was established with molecular dynamic simulation studies for both Site I and Site III interaction. In addition, the analysis can significantly help evaluate the effect of various quercetin-containing foods and supplements during the ERL-treatment regimen. In vitro binding evaluation provides a cheaper alternative approach to investigate ligand-protein interaction before clinical studies

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3–14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13–17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC50=6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC50=0.68 μM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC50=1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.Highlights Antitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated. The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors. Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition. Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets

Novel sulindac derivatives: synthesis, characterisation, evaluation of antioxidant, analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibition activity

A new series of N′-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)−5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide derivatives (1 – 25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R = 3-methoxyphenyl), 3 (R = 4-dimethylaminophenyl) and 23 (R = 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3, with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX‐2 gene expression

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold (HI 5) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound. Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies. Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers (syn and anti) is responsible for binding affinity and intrinsic activity of HI 5. However, the molecular dynamic studies have confirmed that the syn-isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity. Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer