Drug Binding Mode Research Articles

Computational Analysis of S1PR1 SNPs Reveals Drug Binding Modes Relevant to Multiple Sclerosis Treatment.

Background/Objectives: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by myelin and axonal damage with a globally rising incidence. While there is no known cure for MS, various disease-modifying treatments (DMTs) exist, including those targeting Sphingosine-1-Phosphate Receptors (S1PRs), which play important roles in immune response, CNS function, and cardiovascular regulation. This study focuses on understanding how nonsynonymous single nucleotide polymorphisms (rs1299231517, rs1323297044, rs1223284736, rs1202284551, rs1209378712, rs201200746, and rs1461490142) in the S1PR1's active site affect the binding of endogenous ligands, as well as different drugs used in MS management. Methods: Extensive molecular dynamics simulations and linear interaction energy (LIE) calculations were employed to predict binding affinities and potentially guide future personalized medicinal therapies. The empirical parameters of the LIE method were optimized using the binding free energies calculated from experimentally determined IC50 values. These optimized parameters were then applied to calculate the binding free energies of S1P to mutated S1PR1, which correlated well with experimental values, confirming their validity for assessing the impact of SNPs on S1PR1 binding affinities. Results: The binding free energies varied from the least favorable -8.2 kcal/mol for the wild type with ozanimod to the most favorable -16.7 kcal/mol for the combination of siponimod with the receptor carrying the F2055.42L mutation. Conclusions: We successfully demonstrated the differences in the binding modes, interactions, and affinities of investigated MS drugs in connection with SNPs in the S1PR1 binding site, resulting in several viable options for personalized therapies depending on the present mutations.

Molecular Dynamics Unveils Multiple-Site Binding of Inhibitors with Reduced Activity on the Surface of Dihydrofolate Reductase.

The sensitivity to protein inhibitors is altered by modifications or protein mutations, as represented by drug resistance. The mode of stable drug binding to the protein pocket has been experimentally clarified. However, the nature of the binding of inhibitors with reduced sensitivity remains unclear at the atomic level. In this study, we analyzed the thermodynamics and kinetics of inhibitor binding to the surface of wild-type and mutant dihydrofolate reductase (DHFR) using molecular dynamics simulations combined with Markov state modeling. A strong inhibitor of methotrexate (MTX) showed a preference for the active site of wild-type DHFR with minimal binding to unrelated (secondary) sites. Deletion of a side-chain fragment in MTX largely destabilized the active site-bound state, with clear evidence of binding to secondary sites. Similarly, the F31V mutation in DHFR diminished the specificity of MTX binding to the active site. These results reveal the presence of multiple-bound states whose stabilities are comparable to or higher than those of the unbound state, suggesting that a reduction in the binding affinity for the active site significantly elevates the fractions of these states. This study presents a theoretical model that more accurately interprets the altered drug sensitivity than the traditional two-state model.

How accurately can one predict drug binding modes using AlphaFold models?

Computational prediction of protein structure has been pursued intensely for decades, motivated largely by the goal of using structural models for drug discovery. Recently developed machine-learning methods such as AlphaFold 2 (AF2) have dramatically improved protein structure prediction, with reported accuracy approaching that of experimentally determined structures. To what extent do these advances translate to an ability to predict more accurately how drugs and drug candidates bind to their target proteins? Here, we carefully examine the utility of AF2 protein structure models for predicting binding poses of drug-like molecules at the largest class of drug targets, the G-protein-coupled receptors. We find that AF2 models capture binding pocket structures much more accurately than traditional homology models, with errors nearly as small as differences between structures of the same protein determined experimentally with different ligands bound. Strikingly, however, the accuracy of ligand-binding poses predicted by computational docking to AF2 models is not significantly higher than when docking to traditional homology models and is much lower than when docking to structures determined experimentally without these ligands bound. These results have important implications for all those who might use predicted protein structures for drug discovery.

How accurately can one predict drug binding modes using AlphaFold models?

Computational prediction of protein structure has been pursued intensely for decades, motivated largely by the goal of using structural models for drug discovery. Recently developed machine-learning methods such as AlphaFold 2 (AF2) have dramatically improved protein structure prediction, with reported accuracy approaching that of experimentally determined structures. To what extent do these advances translate to an ability to predict more accurately how drugs and drug candidates bind to their target proteins? Here, we carefully examine the utility of AF2 protein structure models for predicting binding poses of drug-like molecules at the largest class of drug targets, the G-protein-coupled receptors. We find that AF2 models capture binding pocket structures much more accurately than traditional homology models, with errors nearly as small as differences between structures of the same protein determined experimentally with different ligands bound. Strikingly, however, the accuracy of ligand-binding poses predicted by computational docking to AF2 models is not significantly higher than when docking to traditional homology models and is much lower than when docking to structures determined experimentally without these ligands bound. These results have important implications for all those who might use predicted protein structures for drug discovery.

Enhancing Ezetimibe Anticancer Activity Through Development of Drug Nano-Micelles Formulations: A Promising Strategy Supported by Molecular Docking.

Ezetimibe, initially recognized as a cholesterol-lowering agent, has recently attracted attention due to its potential anticancer properties. We aimed to explore an innovative approach of enhancing the drug anticancer activity through the development of drug nano-formulations. Fifteen different nano-micelles formulations were prepared utilizing D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and pluronic F127. The prepared formulations were characterized for size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The formulations were morphologically characterized using light and transmission electron microscopies and the drug-binding mode with the active site was investigated using the molecular docking. Cell viability against MCF-7 and T47D was studied. Apoptosis and cell cycle were assessed. The prepared formulations were in the nano-size range (34.01 ± 2.00-278.34 ± 9.11 nm), zeta potential values were very close to zero, and the TPGS-based micelles formulations showed the highest ezetimibe EE (94.03 ± 1.71%). Morphological study illustrated a well-defined, spherical nanoparticles with a uniform size distribution. Molecular docking demonstrated good interaction of ezetimibe with Interleukin-1 Beta Convertase through multiple hydrogen bonding, covalent bond, and hydrophobic interaction. TPGS-based nano-micelle formulation (F5) demonstrated the lowest IC50 against MCF-7 (4.51 µg/mL) and T47D (8.22 µg/mL) cancer cells. When T47D cells were treated with IC50 concentrations of F5, it exhibited significant inhibition with late apoptosis (43.9%), a response comparable to T47D cells treated with an IC50 dose of ezetimibe. Cell cycle analysis revealed that both ezetimibe and F5-treated T47D cells exhibited an increase in the subG1 phase, indicating reduced DNA content and cell death. These findings suggest that F5 could serve as a proficient drug delivery system in augmenting the cytotoxic activity of ezetimibe against breast cancer.

Fluorescence Spectroscopy: A Useful Method to Explore the Interactions of Small Molecule Ligands with DNA Structures.

Small molecule ligands-DNA interactions have recently received a lot of attention in the fields of life sciences, medicine, and chemical sciences. To decode these interactions, many strategies have been developed. DNA is the primary target for a wide range of drugs that may interact with DNA in particular or non-specific ways and impact its activities. Fluorescence spectroscopy is a highly advanced and non-invasive technology for measuring the concentrations of substrates and products or identifying characteristic processing states. Small molecule ligands-DNA interaction studies are beneficial not only in comprehending the method of interaction, but also in synthesizing DNA-targeted particular drugs. Several small compounds that bind to DNA are clinically established therapeutic medicines, while their specific mechanism of action is unknown. Figuring out their molecular recognizing patterns is the only way to construct innovative compounds that can target specific DNA sequences with strong affinities. This book chapter will mostly explore several fluorescence spectroscopic methodologies used to investigate interactions between small molecule ligands and DNA. In addition, we provide many approaches for determining a drug's binding mode with DNA. These strategies produce data that is both trustworthy and easy to comprehend. All of the knowledge gained by studying these fluorescence spectroscopies are supposed to lead to the development of more efficient new pharmaceuticals that might aid in the treatment of diseases.

Molecular Aspects of C-glycosides: Interactive Analysis of C-linked Compounds With the SGLT2 Molecular Model.

Interaction analysis between modeled human sodium/glucose cotransporter 2 (hSGLT2) and antidiabetic C-glycoside drugs, such as canagliflozin, dapagliflozin, ipragliflozin, empagliflozin, tofogliflozin, and luseogliflozin was performed. The hSGLT2 was modeled using the X-ray data of Vibrio parahaemolyticus SGLT2 (protein data bank ID=2XQ2) as a template. Conformational analyses of C-glycosides were performed using CAChe-Conflex. Interactive analyses between hSGLT2 and C-glycosides were performed using Molegro Virtual Docker. Canagliflozin interacted with hSGLT2 via Asn75, Ser287, Lys321 and Gln457 Dapagliflozin interacted with six amino acids (Arg46, Arg49, Ile76, Ser78, Met216 and Ser393). Ipragliflozin (Ala69, Met596 and Gln600), empagliflozin (Ser78, Gly79, Lys154, Asp158 and Ser393), tofogliflozin (Arg49, Met216, Ala389, Ser392 and Ser393), and luseogliflozin (Arg49, Ser74, Ser78, Gly79, His80, Lys154, Asp158 and Ser393) interacted with hSGLT2 via the amino acids described in the parentheses. The binding mode of each C-glycoside drug to hSGLT2 was different, and structural features of each compound were revealed. The reactive base points of C-glycosides were the sugar moiety, with the sugar structure being important for hSGLT2 inhibitory action.

Gemcitabine drug intercalation with ds-DNA at surface of ds-DNA/Pt–ZnO/SWCNTs/GCE biosensor: A DNA-biosensor for gemcitabine monitoring confirmed by molecular docking study

Herein, a facile and highly sensitive electroanalytical tool for monitoring and quantifying the antineoplastic drug gemcitabine in real sample was provided. In this regard, a novel DNA-biosensor based on Pt-doped ZnO decorated single walled carbon nanotubes (Pt–ZnO/SWCNTs) hybrid nanomaterial modification of glassy carbon electrode (GCE) was fabricated. Ds-DNA (Calf Thymus), as a biological recognition element, was decorated onto nanomaterial-modified GCE via layer-by-layer fabrication strategy to attain ultimate biosensor ds-DNA/Pt–ZnO/SWCNTs/GCE. The characterizations confirmed the successful fabrication of hybrid nanomaterial, as well as the modification of electrode surface by fabricated nanomaterial. The electrochemical impedance spectroscopy (EIS) analysis revealed that the nanomaterial modification of GCE surface enhanced the electrical conductivity thanks to the synergistic effects of Pt–ZnO and SWCNTs structures, thereby boosted the electrocatalytic activity of the resultant biosensor. The electrochemical characterization results showed that the suggested biosensor is capable of detecting gemcitabine in a wide concentration range of 0.01–30.0 μM, with a detection limit of 5.0 nM. The intercalation binding mode of Gemcitabine inside guanine and cytosine rich region of DNA receptor was approved by molecular docking study. The results of the experimental data were well congruent with the molecular docking analysis, which showed that the binding mode of gemcitabine drug with ds-DNA was intercalation.

Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ

Targeting the PI3K isoform p110δ against B cell malignancies is at the mainstay of PI3K inhibitor (PI3Ki) development. Therefore, we generated isogenic cell lines, which express wild type or mutant p110δ, for assessing the potency, isoform-selectivity and molecular interactions of various PI3Ki chemotypes. The affinity pocket mutation I777M maintains p110δ activity in the presence of idelalisib, as indicated by intracellular AKT phosphorylation, and rescues cell functions such as p110δ-dependent cell viability. Resistance owing to this substitution consistently affects the potency of p110δ-selective in contrast to most multi-targeted PI3Ki, thus distinguishing usually propeller-shaped and typically flat molecules. Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design.

Structural mapping of Nav1.7 antagonists

Voltage-gated sodium (Nav) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Nav channels, the binding mode of most Nav-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Nav1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Nav channels summarized from the present and previous structures.

Design, synthesis and molecular docking studies of 5,6-difluoro-1H-benzo[d]imidazole derivatives as effective binders to GABAA receptor with potent anticonvulsant activity

In the search for more effective and safer antiepileptic drugs, a series of 5,6-difluoro-1H-benzo[d]imidazole derivatives (4a-e) were designed and synthesized. Elemental analysis, 1H NMR, 13C NMR and mass spectroscopic techniques were used to confirm the structure and purity of the resultant compounds. Maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screenings were used in mice for preliminary anticonvulsant screening. In each of the animals used for anticonvulsant assessment, two compounds, 4d and 4e, demonstrated positive anticonvulsant activity with 100% protection. The most active congeners, compounds 4d and 4e, were quantified to be 2.68 and 3.26 folds, respectively, more potent than the reference medication, carbamazepine, in the MES model. The rotarod technique was used to test all the substances for acute neurotoxicity to detect motor impairment, and all the substances passed the test. Additionally, the in vitro binding studies revealed that compounds 4d and 4e had the most affinity for binding to the GABAA receptor, with IC50 values of 0.74 and 0.18 μM, respectively. Additionally, the GABA concentration in rat brains was examined. The findings indicated that both compounds 4d and 4e may have influenced the GABA system by raising GABA concentration in rat brains. The GABAA receptor and drug binding modes were examined using molecular docking. Compounds 4d and 4e demonstrated substantial interactions with residues at the GABAA receptor's benzodiazepine binding site. According to Lipinski's rule of five, all the compounds show promise as potential oral medication candidates. Thus, the current study has offered suitable epilepsy research subjects for further study.

In vitro Analytical Techniques as Screening Tools to investigate the Metal chelate‐DNA interactions

AbstractDeoxyribose nucleic acid (DNA) is found to be the most efficient pharmacological target of many synthetic molecules which are deemed as potential drugs with clinical applications. DNA binding agents are known to regulate several cell functions (gene expression and replication) by adopting various protocols which include the annihilation of the cell membrane, interruption in protein synthesis, and irreversible binding to cell receptors. Recently, several studies have explored fundamental aspects of drug‐DNA interactions, providing new insights into the driving forces that render the formation of the drug‐DNA complex. In order to study and understand these biologically important reaction mechanisms, several screening tools have been devised and the specificity of drug molecules binding to DNA were studied in detail. This review will discuss the utilization of various analytical tools which include UV‐vis spectroscopy, fluorescence spectroscopy, circular dichroism, viscosity measurement, Raman spectroscopy, cyclic voltammetry, and DNA fragmentation assay used for studying drug binding mode and the mechanism involved.

The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels.

ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATP inhibitors have been prescribed for diabetes and KATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity. SIGNIFICANCE STATEMENT: ATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATP channels are important drug targets. Both KATP inhibitors (insulin secretagogues) and KATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATP structural pharmacology.

Abstract 5239: Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation

Abstract Purpose: MET fusions are oncogenic drivers of multiple cancers including non-small cell lung cancer (NSCLC). While MET fusion-positive tumors can be sensitive to MET tyrosine kinase inhibitors (TKI), to date no mechanisms of TKI resistance have been identified or characterized for MET fusion-positive disease. Experimental Design: Serial targeted genomic sequencing (MSK-IMPACT) was performed in clinical samples from a MET fusion-positive NSCLC treated with the type Ia MET TKI crizotinib. Structural modeling and in vitro kinase assays were used to characterize crizotinib resistance and to test the activity of MET inhibitors with alternative binding modes. Results: A novel MET G1090A resistance mutation was identified in a patient with a CD47-MET-rearranged NSCLC after crizotinib progression. In silico structural modeling and simulations indicated that the 2,6-dichloro-3-fluorophenyl moiety present on crizotinib directly binds to the side chain of the Y1230 residue in the activation loop of the MET wild type (WT) kinase. In the MET G1090A mutant kinase, the position of the Y1230 residue is predicted to be flipped roughly 180°. As a result, the interaction between crizotinib and Y1230 is compromised; this in turn is predicted to reduce crizotinib’s binding affinity for the mutant kinase. Similar results were obtained when MET WT and G1090A mutant kinases were modeled in complex with selective type Ib MET TKI (i.e., capmatinib, savolitinib and tepotinib). Conversely, we found that type II agents (i.e., cabozantinib and foretinib) were not predicted to interact with Y1230. Therefore, their binding affinity to the mutant MET kinase was predicted to be retained. In vitro kinase assays performed using titrations of crizotinib and capmatinib (representative type I agents) and of cabozantinib (representative type II agent) showed that all three TKI were active against the MET WT kinase (calculated IC50 of 2.5nM, 3.89nM and 1.59nM, respectively). However, the calculated IC50 for crizotinib and capmatinib were 6.04- and 48.4-fold higher than the calculated IC50 for cabozantinib against the MET G1090A mutant kinase. Consistent with the prediction of type II inhibitor activity, the patient was transitioned to cabozantinib. A marked clinical, radiographic, and metabolic response was observed. Conclusions: In MET fusion-positive cancers, the novel MET G1090A resistance mutation drives resistance to type I MET kinase inhibition. Drug binding mode switching to type II MET inhibition overcomes preclinical and clinical resistance, highlighting the need for further rational type II inhibitor development. Citation Format: Yonina R. Murciano-Goroff, Srinivasaraghavan Kannan, Jason C. Chang, Ryma Benayed, Ilya Blokhin, Natasha Rekhtman, Ann Elizabeth Sisk, Jaime Gibson, Lia Judka, Lauren Kaplanis, Madeline Merrill, Erica Sgroe, Chandra S. Verma, Alexander Drilon, Emiliano Cocco. Switching inhibitor class overcomes crizotinib resistance in a MET fusion-positive NSCLC with a novel acquired MET G1090A mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5239.

Recent Advances in the Development of Triose Phosphate Isomerase Inhibitors as Antiprotozoal Agents.

Parasitic diseases caused by protozoa, such as Chagas disease, leishmaniasis, malaria, African trypanosomiasis, amoebiasis, trichomoniasis, and giardiasis, are considered serious public health problems in developing countries. Drug resistance among parasites justifies the search for new therapeutic drugs, and the identification of new targets becomes a valuable approach. In this scenario, the glycolysis pathway, which converts glucose into pyruvate, plays an important role in the protozoa energy supply, and it is therefore considered a promising target. In this pathway, triose phosphate isomerase (TIM) plays an essential role in efficient energy production. Furthermore, protozoa TIM shows structural differences with human enzyme counterparts, suggesting the possibility of obtaining selective inhibitors. Therefore, TIM is considered a valid approach to develop new antiprotozoal agents, inhibiting the glycolysis in the parasite. In this review, we discuss the drug design strategies, structure-activity relationship, and binding modes of outstanding TIM inhibitors against Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, Giardia lamblia, Leishmania mexicana, Trichomonas vaginalis, and Entamoeba histolytica. TIM inhibitors have mainly shown aromatic systems and symmetrical structure, where the size and type of heteroatom are important for enzyme inhibition. This inhibition is mainly based on the interaction with i) the interfacial region of TIM inducing changes on the quaternary and tertiary structure or ii) with the TIM catalytic region, the main pathways that disable the catalytic activity of the enzyme. Benzothiazole, benzoxazole, benzimidazole, and sulfhydryl derivatives stand out as TIM inhibitors. In silico and in vitro studies have demonstrated that the inhibitors bind mainly at the TIM dimer interface. In this review, the development of new TIM inhibitors as antiprotozoal drugs is demonstrated as an important pharmaceutical strategy that may lead to new therapies for these ancient parasitic diseases.

Idarubicin/mithramycin-acridine orange combination drugs co-loaded by DNA nanostructures: Different effects of intercalation and groove binding on drug release and cytotoxicity

The co-loading of chemotherapy-phototherapy (CTPT) combination drugs by aptamer-targeted DNA nanostructures has significant advantages in improving anticancer effects and overcoming the multidrug resistance of cancer cells. The different binding modes of drugs to DNA nanostructures may impact CTPT therapy. Here, the anti-drug resistance effects of idarubicin (IDA) or acridine orange (AO) as single drug, as well as IDA/mithramycin (MTR) dimers ((MTR)2Zn2+) + AO combination drugs loaded by AS1411-tethered DNA nanotrains (AS1411NTrs), were studied. The intercalative binding mode between IDA/AO and AS1411NTrs was verified through measurements of viscosity, changes in melting temperature, and potassium iodide quenching. A series of thermodynamic parameters such as the binding constant and the number of binding sites were obtained through fluorescence spectroscopy, isothermal titration calorimetry, and differential scanning calorimetry. The high binding constants and the number of binding sites indicated that AS1411NTrs had a high loading capacity for IDA and AO. An in vitro release study showed that the release rate and release model of IDA/(MTR)2Zn2+/AO in the binary and ternary systems with or without deoxyribonuclease I were related to their binding mode and order of addition. An in vitro cytotoxicity study proved that the cytotoxicity and synergistic effects of the three drugs to human breast cancer MCF-7 cells and multidrug-resistant MCF-7/ADR cells were enhanced due to loading of AS1411NTrs. The IDA/(MTR)2Zn2+ + AO combination drugs could more obviously enhance apoptosis of MCF-7/ADR cells as confirmed by cell apoptosis assays. The cell uptake study demonstrated that IDA/(MTR)2Zn2+/AO loaded by AS1411NTrs was mainly concentrated in the nucleus of MCF-7/ADR cells. This work will provide theoretical information for combination therapy of IDA/(MTR)2Zn2+ and AO based on DNA nanostructures.

Quantum Mechanical Study of some Intercalating and Groove Binding Anticancer Drugs with AT and GC Base Pair of DNA Nucleobase

Anticancer drugs bind with DNA nucleobase pairs (AT and GC) through different binding modes such as intercalation, groove binding, covalent binding etc. Quantum mechanical DFT method is quite useful for computing the interaction energy value for anticancer drug-DNA nucleobase complexes. In our study, we have taken some of the anticancer drugs to investigate the interaction energy for drug-DNA complexes. Among the different binding modes of anticancer drugs; minor and major groove binding in DNA base pair is also an important aspect for anticancer drugs; therefore some anticancer drugs may be minor groove specific and some may be major groove specific. Since, such sequence-specific experimental studies for drug-DNA nucleobase complexes are very complicated and hence this may be investigated by using quantum mechanical theoretical studies, using M062X basis set. Our studies reveal that the stacked models of anticancer drugs-DNA nucleobase (AT and GC) complexes always show negative interaction energy values and among all such complexes the most negative interaction energy value results the most stable and favoured stacked systems. The stacking interaction energies for anticancer drugs-DNA nucleobase (AT and GC) complexes can easily be reflected in the interaction of energy plots.

A green and sensitive guanine-based DNA biosensor for idarubicin anticancer monitoring in biological samples: A simple and fast strategy for control of health quality in chemotherapy procedure confirmed by docking investigation

Drug efficiency can be considerably boosted while adverse effects can be reduced by precisely monitoring the concentration of anti-cancer drugs. Thus, one of the most important parameters for human health is the monitoring and detection of anticancer drugs during chemotherapy treatment. Herein, a glassy carbon electrode (GCE) was modified by Pt- and Pd-incorporated ZnO nanoparticles-decorated single-wall carbon nanotubes (Pt–Pd–ZnO/SWCNTs) nanocomposites, and ds-DNA (Calf Thymus) that was a biological recognition element, and it was aimed to be utilized as an ultrasensitive and effective electroanalytical biosensor for idarubicin (IDR) monitoring. Various physicochemical characterization techniques including transmission electron microscopy (TEM), field-emission scanning electron microscopy (FE-SEM) with energy-dispersive X-ray spectroscopy (EDS) were used to investigate the morphology and structure of the Pt–Pd–ZnO/SWCNTs nanocomposite, which was produced via straightforward chemical precipitation combined with the one-pot method. The layer-by-layer modification technique was implemented to fabricate the ds-DNA/Pt–Pd–ZnO/SWCNTs/GCE to be further utilized as a voltammetric sensor for sensitive monitoring of idarubicin in biological fluids and pharmaceutical substances. The electroanalytical method implemented to detect idarubicin was based to detect the ds-DNA's guanine base signal on the surface of the modified electrode in the absence and presence of the anticancer drug. The results explicated that the developed biosensor performed well in determining idarubicin in concentrations ranging from 1.0 nM to 65 μM, with a detection limit of 0.8 nM. The idarubicin detection ability of the modified electrode in real samples was evaluated, and the recovery data was acquired in the range of 98.0% and 104.75%. In the final step, the preferential intercalative binding mode of idarubicin drug with ds-DNA was approved by molecular docking study. This study paves the way for engineering highly sensitive DNA biosensors to be employed in the monitoring of anticancer drugs by combining the benefits of nanocomposites and valuable information of a molecular docking study.

Interactions of Aminopropyl–Azithromycin Derivatives, Precursors in the Synthesis of Bioactive Macrozones, with E. coli Ribosome: NMR and Docking Studies

The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. 13C and 15N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.

Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.

State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.