Molecular Docking Interaction Research Articles

Synthesis, antifungal studies, molecular docking, ADME and DNA interaction studies of 4-hydroxyphenyl benzothiazole linked 1,2,3-triazoles

In search of new bioactive 1,2,3-triazole hybrids, some 4-hydroxyphenyl benzothiazole (4-HBT) linked 1,2,3-triazole with varying lengths of alkyl spacers were synthesized from bromo alkoxy derivatives of 4-HBT. All the synthesized hybrids were satisfactorily characterized, and were evaluated for in-vitro antifungal activity against C. tropicalis and A. terreus fungal strains wherein compound 4 h showed better activity for both fungal strains compared to the reference drug Fluconazole. Molecular docking with the active site of 14α-sterol demethylase enzyme (PDBID: 1EA1) showed that all compounds exhibited strong H-bonding interactions with Thr260, Ala256, Arg96, Phe78, Leu321, Tyr76 while compound 4 h with the lone pair of -Cl have shown better interaction with the active site and were involved in H-bond interaction with THR 260. DNA binding study exhibited very good DNA-interaction (2.03 × 105 Lmol-1) of compound 4b with the hs-DNA. The results of DFT study and ADME investigations were accessed for the pharmacodynamics and pharmacokinetic properties of the synthesized molecules.

Investigation on electronic structure, vibrational spectra, NBO analysis, and molecular docking studies of aflatoxins and selected emerging mycotoxins against wild-type androgen receptor

The geometry, frontier molecular orbitals (FMOs), vibrational, NBO analysis, and molecular docking simulations of aflatoxins (B1, B2, M1, M2, G1, G2), zearalenone (ZEA) emodin (EMO), alternariol (AOH), alternariol monoethyl ether (AMME), and tenuazonic acid (TeA) mycotoxins have been extensively theoretically studied and discussed based on quantum density functional theory calculations using Gaussian 16 software package. The theoretical computation for the geometry optimization, NBOs, and the molecular docking interaction was conducted using Density Functional Theory with B3LYP/6-31+G(d,p), NBO program, and AutoDock Vina tools respectively. Charge delocalization patterns and second-order perturbation energies of the most interacting natural bond orbitals (NBOs) of these mycotoxins have also been computed and predicted. Interestingly, among the mycotoxins investigated, aflatoxin G1 is seen to give the strongest stabilization energy while Zearalenone shows the highest tendency to accept electron(s) and emodin, an emerging mycotoxin gave the best binding pose within the androgen receptor pocket with a mean binding affinity of -7.40 kcal/mol.

Tea catechin as antiviral agent via apoptosis agonist and triple inhibitor mechanism against HIV-1 infection: A bioinformatics approach

Context: Human immunodeficiency virus (HIV) antiretrovirals that target the binding of viral enzyme are chosen as the lead solution in the treatment of HIV-1 infection, such as non-catalytic site integrase inhibitor (NCINI), nevirapine, and darunavir. There are natural compounds from specific plants that can be effective in treating HIV-1 infection such as tea catechin. Tea catechin administration causes a decrease in viral load and inhibition of entry mechanisms and an increased effect of apoptosis in infected cells. Aims: To identify the triple inhibitor mechanism in tea catechins against the three HIV-1 enzymes and apoptosis agonists through in silico approach as an innovation in handling HIV-1 infection. Methods: The 3D structure of tea catechin compounds from the database was examined, and then all target compounds were analyzed for drug-likeness, molecular docking, pathway prediction, and molecular interactions to determine the potential of tea catechin compounds as antiviral HIV-1 in silico. Results: Tea catechin compounds have the potential to serve as antiviral against HIV-1 through apoptosis agonist and triple inhibitor mechanisms. Apoptosis occurs due to the interaction of tea catechins with pro-apoptotic proteins in cells, and the epigallocatechin gallate (EGCG) compound is a class of tea catechins with the same binding position as control. Conclusions: The binding of the EGCG molecule complex results in low binding energy. Therefore, it allows EGCG acts as a triple inhibitor in HIV-1 infection.

Spectral, modeling and biological studies on a novel (E)-3-(3‑bromo-4-methoxyphenyl)-1-(thiazol-2-yl)prop‑2-en-1-one and some bivalent metal(II) complexes

A thiazole-based chalcone ligand (E)-3-(3‑bromo-4-methoxyphenyl)-1-(thiazol-2-yl)prop‑2-en-1-one(BMTP) and its Co(II), Ni(II), Cu(II) and Zn(II) complexes have been synthesized. The synthesized compounds were characterized by elemental analyses, FT-IR, NMR, mass, molar conductance, UV–Vis, magnetic susceptibility, and thermal techniques. The title compounds were optimized with Density Functional Theory (DFT) computations. The Lewis base character of BMTP, flexibility towards metal ions, structural stabilization on coordination, molecular orbital interactions, quantum chemical descriptors, and vibrational frequencies were evaluated. The compounds were screened for antimicrobial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Aspergillus flavus and Candida albicans. Metal complexes exhibit higher microbial toxicity than the free ligand. The molecular docking interactions were found to be in good agreement with the experimental microbial activities.

Design, Synthesis, Antimicrobial and Anticancer Activity of some Novel Benzoxazole-Isatin Conjugates

A series of novel benzoxazole-isatin conjugates were synthesized by treating 2-amino benzoxazole with 5 and 7 substituted isatin derivatives and were screened for in vitro antimicrobial and cytotoxic activities. The results showed that all the synthesized compounds shown mild to potent antibacterial activity. The MIC values were found between 10 and 100 µg/ml against tested bacterial and fungal organisms. Among all the compounds, 3d & 3c showed good antimicrobial. In vitro cytotoxic activities were evaluated by MTT assay of all the test compounds against the different human cancer cell lines. The compounds having substitution with electron-withdrawing groups (halides) at the 5th position on the isatin ring showed the most significant biological activity than substituted at the 7th position. The molecular docking interactions have shown good binding interactions with the protein targets glucosamine-6-phosphate synthase (GlcN-6-P synthase) and telomerase.

Modifying the catalytic preference of alpha-amylase toward n-alkanes for bioremediation purposes using in silico strategies.

Since the beginning of oil exploration, whole ecosystems have been affected by accidents and bad practices involving petroleum compounds. In this sense, bioremediation stands out as the cheapest and most eco-friendly alternatives to reverse the damage done in oil-impacted areas. However, more efforts must be made to engineer enzymes that could be used in the bioremediation process. Interestingly, a recent work described that α-amylase, one of the most evolutionary conserved enzymes, was able to promiscuously degrade n-alkanes, a class of molecules abundant in the petroleum admixture. Considering that α-amylase is expressed in almost all known organisms, and employed in numerous biotechnological processes, using it can be a great leap toward more efficient applications of enzyme or microorganism-consortia bioremediation approaches. In this work, we employed a strict computational approach to design new α-amylase mutants with potentially enhanced catalytic efficiency toward n-alkanes. Using in silico techniques, such as molecular docking, molecular dynamics, metadynamics, and residue-residue interaction networks, we generated mutants potentially more efficient for degrading n-alkanes, L183Y, and N314A. Our results indicate that the new mutants have an increased binding rate for tetradecane, the longest n-alkane previously tested, which can reside in the catalytic center for more extended periods. Additionally, molecular dynamics and network analysis showed that the new mutations have no negative impact on protein structure than the WT. Our results aid in solidifying this enzyme as one more tool in the petroleum bioremediation toolbox.

Synthesis, characterization, in vitro and in silico studies of bis-hydrazone complexes derived from terephthalic dihydrazide

Bis-hydrazone of terephthalic dihydrazide was designed and synthesized using terephthalic dihydrazide and picolinaldehyde. Various bioactive benzoic acids such as benzoic acid, aspirin and salicylic acid were selected as a counter ion moiety for preparing bis-hydrazone complexes (BHCs). The prepared BHCs were well characterized using spectroscopic techniques like 1H NMR, 13C NMR and FT-IR. The BHCs showed very good in vitro antidiabetic activity in the α-amylase enzyme inhibitory method and moderate activity in the α-glucosidase inhibitory method. The molecular docking interactions of BHCs were performed against the human pancreatic α-amylase enzyme (1HNY.pdb) and homology model of α-glucosidase (3A4A.pdb) to prove the enzyme inhibitory activity. The BHCs showed very good binding energy, the complex BHB showed 5 numbers of hydrogen bonding interactions with amino acid residues of 1HNY.pdb and BHS showed 5 numbers of hydrogen bonding interactions with 3A4A.pdb. Further, the molecular orbital studies were performed using density functional theory calculations in order to support the docking study.

Metal based nanoparticles trigger the differential expression of key regulatory genes which regulate iron and zinc homeostasis mechanism in finger millet

Since green revolution, the food systems in most of the countries have dramatically changed but undernourishment still remains an inflammable problem. This alarming condition is even increasing due to the marginal supply of nutri-enriched food to eat. Under such chronically undernourished condition, dietary deficiencies of iron and zinc lead to compromised planetary health and economic losses. Given the micronutrient deficiency, there is an urgent call to devise or innovative a strategy for providing the requisite amount of iron and zinc in their daily intake to counter this issue. Thus being a high iron and zinc accumulating crop, finger millet can be efficiently used as an intricate model system to explore the prospects of genetic and molecular mechanisms which are responsible for nutrient enrichment in grains. We report here a promising role of nanotechnology in terms of their iron and zinc biofortification potentials in the finger millet. Comparative in vitro evaluation using lower concentration of Fe3O4 (100 ppm) and ZnO (5 ppm) nanoparticles (NPs) display a significant promotory effect on both mineral assimilation and growth parameters whereas higher concentrations of NPs, FeSO4.7H2O and ZnSO4.7H2O bulk salts marked inhibitory effects. The molecular modelling and docking interaction analysis infers that these nano-minerals may bind to significantly influence the modulation of regulatory genes. The result was further validated using real time PCR profiling. The differential expression profiling resulted in higher transcriptional modulation of iron and zinc transporters particularly EcFER1, EcIRT2, EcYSL2, EcZIP1 and EcZTP29 in nano-primed genotypes compared to controls. Thus in conclusion, being a nutrient by default and stress-resilient crop, nanoparticle formulations in finger millet triggers the epigenetic regulation of potential key regulatory genes involved in iron and zinc homeostasis. The study also indicates innovative role of nano-seed priming for biofortification which triggers differential modulation of iron and zinc acquisition and enrichment in grains despite nutrient limiting conditions.

A study on MAPK/ERK and CDK2-Cyclin-E signal switch “on and off” in cell proliferation by bis urea derivatives of 1, 4-Diisocyanatobenzene

A series of novel substituted bisurea 1,4-Diisocyanatobenzene compounds were designed, synthesized and introduced as potent anticancer compounds and screened for their in vitro anti-proliferative activities in human cancer cell lines. The structures of all titled compounds were characterized using Fourier-transform infrared mass spectra, nuclear magnetic resonance spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. A selected group of ten derivatives were apprised for their anti-proliferative activity. The compounds 3d and 3e displayed potent anticancer activity with low IC50 value of 5.40, and 5.89 μM against HeLa cancer cell lines. The observed apoptosis data has demonstrated that compounds 3d and 3e induce the activaties of caspase-9 and caspase-3, the compounds 3d and 3e regulated fungal zone inhibition. Due to promising growth inhibitions, the all synthesized compounds were allowed to campaign includes quantum-polarized-ligand, quantum mechanical and molecular mechanical, docking experiments. The compounds 3d and 3e have exhibited a higher affinity for ERK/MAP kinase and CDK2 proteins. The molecular docking interactions have demonstrated two stage inhibition of cancer cells by binding with ERK/MAP kinase and CDK2 leads to inactivation of cell proliferation,cell cycle progression,cell divisionanddifferentiation, and hypo-phosphorylation of ribosome leading cells to restricts at point boundary of the G1/S phase. The long-range molecular dynamics, 150 ns, simulations were also revealed more consistency by 3d. Our study conclude good binding propensity for active-tunnel of ERK/MAP kinase and CDK2 proteins, by 3d (1,1′-(1,4-phenylene) bis(3-(2-chlorobenzyl)urea)), to suggest that the designed and synthesized 3d is to use as selective novel nuclei in anti-cancer chemotherapeutics.

The Antihypertensive Effects and Potential Molecular Mechanism of Microalgal Angiotensin I-Converting Enzyme Inhibitor-Like Peptides: A Mini Review.

Hypertension causes many deaths worldwide and has shown an increasing trend as a severe non-communicable disease. Conventional antihypertensive drugs inevitably cause side effects, and great efforts have been made to exploit healthier and more-available substitutes. Microalgae have shown great potential in this regard and have been applied in the food and pharmaceutical industries. Some compounds in microalgae have been proven to have antihypertensive effects. Among these natural compounds, peptides from microalgae are promising angiotensin-converting enzyme (ACE) inhibitors because an increasing number of peptides show hypertensive effects and ACE inhibitory-like activity. In addition to acting as ACE inhibitors for the treatment of hypertension, these peptides have other probiotic properties, such as antioxidant and anti-inflammatory properties, that are important for the prevention and treatment of hypertension. Numerous studies have revealed the important bioactivities of ACE inhibitors and their mechanisms. This review discusses the antihypertensive effects, structure-activity relationships, molecular docking studies, interaction mechanisms, and other probiotic properties of microalgal ACE inhibitory peptides according to the current research related to microalgae as potential antihypertensive drugs. Possible research directions are proposed. This review contributes to a more comprehensive understanding of microalgal antihypertensive peptides.

PEPPSI complexes as potential prodrugs: enzyme inhibition, antioxidant activity, electrochemical characterization, molecular docking analysis.

In this study, enzyme inhibition and antioxidant activity analyzes of previously characterized pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI)-type Palladium(II) complexes with benzimidazole-type ligands {dichloro[L]pyridine palladium(II), L1: 1-(2-methyl-2-propenyl)-3-[benzylbenzimidazole]-2-ylidene, L2: 1-(2-methyl-2-propenyl)-3-[4-chloro benzylbenzimidazole]-2-ylidene, L3: 1-(2-methyl-2-propenyl)-3-[3-methylbenzylbenzimidazole]-2-ylidene, L4: 1-(2-methyl-2-propenyl)-3-[3,4,5-thrimethoxybenzylbenzimidazole]-2-ylidene, L5: 1-(2-methyl-2-propenyl)-3-[3-naphthylbenzylbenzimidazole]-2-ylidene, L6: 1-(2-methyl-2-propenyl)-3-[anthracen-9-ylmethylbenzimidazole]-2-ylidene} were performed and evaluated as potential drugs for neurodegenerative disorders such as Alzheimer disease and Parkinson disease. Inhibition of tyrosinase enzyme of N-heterocyclic carbenes (NHC) complexes was determined for the first time in literature. Chelating activities of the complexes were determined and compared with EDTA. Electrochemical characterization was performed using cyclic voltammetry method. Moreover, global reactivity descriptors and electronic transitions were evaluated by DFT/TDDFT methods and molecular docking interactions with human acetylcholine esterase, human butyrylcholine esterase and oxidoreductase were studied.

Integrating Network Pharmacology and Experimental Validation to Decipher the Mechanism of Action of Huanglian Jiedu Decoction in Treating Atherosclerosis.

BackgroundThis study used network pharmacology, molecular docking and experimental validation to assess the effects of Huanglian Jiedu Decoction (HLJDD) on atherosclerosis (AS).MethodsThe components and targets of HLJDD were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and information on the genes associated with AS was retrieved from the GeneCards and OMIM platforms. Protein–protein interactions were analyzed using the STRING platform. A component–target–disease network was constructed using Cytoscape. GO and KEGG analyses were performed to identify molecular biological processes and signaling pathways, and the predictions were verified experimentally. Molecular docking was conducted with ChemOffice software, PyMOL software and Vina to verify the correlation of targets and compounds.ResultsHLJDD contained 31 active compounds, with quercetin, kaempferol, moupinamide and 5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chromone as the core compounds. The most important biotargets of HLJDD in AS were ICAM-1, CD31 and RAM-11. The molecular docking results showed that the molecular docking interaction energy between the 3 key targets and the 4 high-degree components were much less than −5 kJ∙mol−1. The experimental validation results showed that HLJDD might treat AS mainly by reducing TC, TG and LDL-C and increasing HDL-C, upregulating CD31 expression, reducing ICAM-1 and RAM-11 expression, and downregulating inflammatory factors, including CRP, IL-6 and TNF-α. These results support the network pharmacology data and demonstrate that HLJDD affects the expression of core genes and alters the leukocyte transendothelial migration signaling pathway.ConclusionBased on network pharmacology and experimental validation, our study indicated that HLJDD exerted anti-AS effect through upregulating CD31 expression and reducing the expression of ICAM-1 and RAM-11. HLJDD may be a potential therapeutic drug to the prevention of AS.

Synthesis, antioxidant activity and bioinformatics studies of L-3-hydroxytyrosine templated N-alkyl/aryl substituted urea/thioureas

A new series of urea/thiourea derivatives have been efficiently synthesized from the reaction of L-3-hydroxytyrosine with selective isocyanates/isothiocyanates and characterized by Infra-red, proton & carbon-13 nuclear magnetic resonance spectral and mass spectrometry studies. All the synthesized compounds have been screened for their antioxidant activity by 1,1-diphenyl1-2-picrylhydrazyl radical assay, ferric reducing antioxidant power assay and also studied their molecular docking interaction profiles against 1N8Q and 3NRZ enzymatic proteins. The in vitro antioxidant activity has further supported by quantitative structure activity relationship, absorption, distribution, metabolism, and excretion & toxicity studies, bioactivity studies & enzyme inhibition assay and identified that they were potentially bound to ASP490 & ASP361 aminoacid residue in chain A of 1N8Q protein and GLN1194 aminoacid residue in chain L of 3NRZ protein and are responsible for potential antioxidant activity. It is proved that urea derivatives linked with 4-fluoro & 4-nitro and thiourea derivatives linked with 3-chloro & 4-fluoro have exhibited promising antioxidant activity. In eventual synthesized compounds have been identified as potential blood–brain barrier penetrable compounds and proficient central nervous system active neuro-protective antioxidant agents as they have envisaged as easily penetrable to blood–brain barrier thresholds, a neuroprotective property.

Solid-state zwitterionic tautomerization of 2-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-benzimidazole: Synthesis, characterization, DFT calculation and docking studies

The synthesis, characterization and single crystal X-Ray diffraction structure of 2-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-benzimidazole are reported. The physicochemical characterization of the title compound was performed by spectroscopic techniques like FTIR, NMR analysis and single crystal X-ray diffraction. These data, together with the computed vibrational frequencies and NMR chemical shifts at the B3LYP/6–311++G(d,p) level of theory, are in agreement, and the confirmation of the coexistence of the two Zwitterionic tautomer's in the solid-state is proven using X-ray diffraction. The electronic and structural properties were investigated by DFT method at the geometry-optimized B3LYP/6–311++G(d,p) level. The HOMO-LUMO interactions were also studied. In order to explore the biological importance of the compound, molecular docking interactions have been studied to investigate the inhibition properties of the 2-((5-methyl-1H-pyrazol-3-yl)methyl)-1H-benzoimidazole molecule, indicative of the drug likeliness behavior of the synthesized molecule.

Antibiofilm Activity of α-Amylase from Bacillus subtilis and Prediction of the Optimized Conditions for Biofilm Removal by Response Surface Methodology (RSM) and Artificial Neural Network (ANN)

α-amylase is known to have antibiofilm activity against biofilms of both Gram positive and Gram-negative bacterial strains. Partially purified α-amylase from Bacillus subtilis was found to have inhibit biofilm formed by P. aeruginosa and S. aureus. The spectrophotometric and microscopic studies revealed that the antibiofilm efficacy of the working strain is greater than commercially purchased α-amylase. Response surface methodology (RSM) and artificial neural network (ANN) help to predict the optimum conditions [pH 8, treatment time 6h and enzyme concentration (200µg/mL)] for maximum biofilm eradication. This was confirmed by several in vitro experiments. Molecular docking interactions of α-amylase with the extracellular polymeric substances (EPS) of both P. aeruginosa and S. aureus indicate towards the existence of an efficient energy driven spontaneous process. Thus, this study highlights a combination of experimental and computational approach showing the naturally extracted α-amylase from B. subtilis having the potency of removing the biofilms of harmful bacterial strains involved in causing various nosocomial infections.

Acacetin and pinostrobin as a promising inhibitor of cancer-associated protein kinases

Protein kinases associated with cancer genes play vital role in angiogenesis, invasion, motility, proliferation, and survival. Therefore, cancer prevention/treatment, targeting kinases with phytochemicals could be a promising approach. Given potential of phytochemicals in modulating cancer-associated kinases, present study aims to find inhibitory prospects of selected flavonoids for cancer-chemoprevention/treatment. The molecular docking interaction analysis was done by exploring binding potential of flavonoids with kinases (PI3K, Akt, mTOR, EGFR, MAPK, MKK4, Fyn, ZAP-70, B-Raf, JAK-2, STAT-1, STAT-3, STAT-4, STAT-5, and VEGF) involved in various carcinogenesis phases. Among flavonoids acacetin showed highest binding-energy against JAK-2 following Fyn > VEGF > PI3K > MKK4 > MAPK > BRaf > STAT-5 > STAT-1 > STAT-4 whereas pinostrobin depicts higher binding-energy with JAK-2 followed by B-Raf > MKK4 > VEGF > PI3K > MAPK > STAT-1 > STAT-4 > STAT-5. Further, molecular-dynamic simulation revealed that pinostrobin interacted with JAK-2 protein with binding-energy of −25.068 ± 1.08 kJ/mol whereas acacetin interacted with both JAK-2 and Fyn with binding-energies of −23.466 ± 0.9508 kJ/mol and-8.935 ± 1.3108 kJ/mol respectively. High binding-energy, low inhibition-constant, and drug-likeness of acacetin and pinostrobin provide a clue for their usage as a JAK-2 inhibitor which could be useful for molecular/cell-target based in-vitro and in-vivo investigations.

Unveiling the Anti-tubercular Properties of Biscoumarins, through Biological Evaluation and Docking Studies

Background: Biscoumarin scaffolds are known for their promising pharmacological properties. These compounds have not been studied for their activity against tuberculosis strains. Objective: Unveil the antitubercular properties of biscoumarin scaffolds. Methods: Biscoumarin derivatives (3a-3l) were synthesized using lemon juice as a catalyst and were investigated for their in-vitro anti-tubercular activity against the H37Rv strain of Mycobacterium tuberculosis using Microplate Alamar Blue Assay Method (MABA). Their binding interaction was investigated by Molecular Docking Studies using InhA with PDB-ID: 2NSD as target receptors in the H37Rv strain of Mycobacterium tuberculosis. These derivatives (3a-3l) were subjected to the neutrophil function test. Results: The results revealed that compounds 3b, 3c, 3d, 3f, 3i, 3j showed excellent activity with MIC 1.6μg/mL. Molecular docking interactions for their antitubercular activity proved that the derivatives (3a-3l) can easily bind into the pockets of the enzyme. Neutrophil function test signified that they exhibit moderate neutrophil functions assuring that they do not harm the functioning of Neutrophils. Conclusion: These studies have awakened the property of Biscoumarins as promising antitubercular scaffolds.

An Efficient One-Pot Synthesis of 6-Phenyl-3-(1H-Pyrazol-1-yl)-[1,2,4]Triazolo[3,4-b][1,3,4]Thiadiazole Derivatives and Their Antimicrobial Evaluation and Molecular Docking Studies

An efficient rapid synthesis of a new class of diversely functionalized 6-phenyl-3-(1H-pyrazol-1-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (4a–q) is described via a facile one-pot, three-component cascade reaction with high yields. It is a multi-functional cyclization reaction to form two new heterocycles. The structures of newly formed compounds were confirmed by using spectral and analytical studies. Simple reaction conditions, the good isolated yield of the product, and no column chromatographic purification are attractive features of the present protocol. Further, the newly synthesized compounds were screened for anti-microbial activity and molecular docking interactions.

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

The tyrosine kinase inhibitor sorafenib (SOR) is being used increasingly in combination with other anticancer agents like paclitaxel, but this increases the potential for drug toxicity. SOR inhibits several human CYPs, including CYP2C8, which is a major enzyme in the elimination of oncology drugs like paclitaxel and imatinib. It has been reported that CYP2C8 inhibition by SOR in human liver microsomes is potentiated by NADPH-dependent biotransformation. This implicates a SOR metabolite in enhanced inhibition, although the identity of that metabolite is presently unclear. The present study evaluated the capacity of the major N-oxide metabolite of SOR (SNO) to inhibit CYP2C8-dependent paclitaxel 6α-hydroxylation. The IC50 of SNO against CYP2C8 activity was found to be 3.7-fold lower than that for the parent drug (14 μM versus 51 μM). In molecular docking studies, both SOR and SNO interacted with active site residues in CYP2C8, but four additional major hydrogen and halogen bonding interactions were identified between SNO and amino acids in the B–B′ loop region and helixes F’ and I that comprise the catalytic region of the enzyme. In contrast, the binding of both SOR and SNO to active site residues in the closely related human CYP2C9 enzyme was similar, as were the IC50s determined against CYP2C9-mediated losartan oxidation. These findings suggest that the active metabolite SNO could impair the elimination of coadministered drugs that are substrates for CYP2C8, and mediate toxic adverse events, perhaps in those individuals in whom SNO is formed extensively.

Comparative study of cytotoxic activities, DNA binding and molecular docking interactions of anticancer agent epirubicin and its novel copper complex

In this present study, we aimed to prepare a transition metal complex of the commonly accepted anti-cancer agent Epirubicin (EPR). 1:1 complex formation reaction between inorganic salt of Cu(II) and EPR was investigated and performed. The complex formation conditions were studied by employing essential analytical tools and the obtained complex was characterized by using several analytical and spectroscopic techniques such as UV–Vis, FT-IR, LC-MS/MS, and ICP-OES technique was applied for the determination of the percentage metal ion present in the structure. Characterization results were proved the formation of the novel copper complex and clarified its proposed structure. The copper complex of EPR was prepared successfully in strongly alkaline conditions and complex formation was found to be pH-dependent and obtained in a water–methanol mixture with a facile synthesis. The prepared complex was additionally subjected to the cytotoxicity test by applying MTT assay in comparison with EPR and also the binding ability of the EPR and novel complex to fish sperm double strain deoxyribonucleic acid (FSdsDNA) was investigated and the results were indicated that complex could be evaluated as a new promising drug candidate. Based on the compounds docked model, the binding affinities were found to be -9,8 and -9,5 kcal/mol for EPR and copper (II) complex, respectively. The compounds-DNA docked model correlated with our experimental results, and they are groove binders.