Preferred Binding Mode Research Articles

Selective Adsorption of Thiol-Containing Molecules on Copper Sulfide Surfaces via Molecule-Surface Disulfide Bridges.

Recent results in the fields of nanoenhanced agriculture and expanding interest in prebiotic chemistry have placed increased emphasis on understanding the chemically selective interaction of small molecules with the surfaces of metal sulfides. We present an integrated experimental and computational study of the interaction of thiol-containing molecules with copper sulfide (covellite) surfaces in aqueous media. In situ Fourier-transform infrared (FTIR) measurements and ex situ X-ray photoelectron spectroscopy (XPS) measurements show that molecules bearing free thiol groups, including glutathione and cysteine, bind strongly to CuS (covellite) nanoparticles and to CuS (001) single crystals, while control studies show that similar molecules lacking the free thiol group exhibit much less binding. Additional experiments show that these thiol-containing molecules interact transiently with CuO nanoparticle surfaces but are readily removed by rinsing. The FTIR and XPS experiments demonstrate that adsorption of molecular thiols to CuS surfaces occurs in a chemically selective manner. Further experimental studies and density functional calculations show that the preferred mode of binding is through the surface S atoms, forming a Solid-S-S-Molecule disulfide linkage. While the role of disulfide linkages in controlling structure and function of proteins and other biomolecules is widely known, the formation of surface disulfide linkages as a motif for covalent molecular binding at surfaces has not been established previously.

Raubasine-Induced Groove Binding in Salmon Testes DNA: Exploring the Structural Modulation, Antiglycation, and Antioxidant Properties.

As one of nature's most fundamental blueprints and due to its critical role in life processes, DNA has naturally become the cornerstone of numerous research efforts. One particularly intriguing area of study is understanding how small molecules interact with nucleic acids. In this study, we investigated the interaction between the plant-derived indole alkaloid Raubasine (Ajmalicine; AJM) and Salmon Testes (ST) DNA using biophysical and computational techniques. A hyperchromic shift in the fluorescence intensity indicated the effective binding of AJM to ST DNA. The binding constant was in the order of 105 M-1 with a single preferential binding mode. Thermodynamic analysis revealed that exothermic binding was driven by positive entropy and negative enthalpy. The salt-dependent fluorescence analysis indicates the involvement of nonpolyelectrolytic forces in the interaction. Studies of iodide quenching, urea denaturation, dye displacement, and molecular docking further support that AJM binds to ST DNA through groove binding. Structural perturbation of DNA was evident from circular dichroism. The stability of the AJM-DNA complex was confirmed by molecular dynamics simulations. Prolonged elevated blood glucose levels induce nonenzymatic glycation of DNA, resulting in DNA-AGE (advanced glycation end-products) formation and free radical production, which disrupts the DNA structure. We explored ST-DNA glycation and its suppression by AJM. DNA-AGEs in vitro were characterized using UV-vis and fluorescence spectroscopy. The inhibition of glycation by AJM was assessed through changes in AGEs fluorescence intensity, gel electrophoresis patterns, and antioxidant activity, highlighting its ability to target glycated sites or neutralize free radicals generated during glycation. Our findings reveal AJM's potential to prevent the formation of AGEs, which may offer promising avenues for targeted therapies against glycation-related diseases such as diabetes, neurodegeneration, and cancer.

Tuning Intermolecular Interactions for Chiral Analysis: The Microwave Spectra and Molecular Structures of the Chiral Tag Candidates cis- and trans-2-Fluoro-3-(trifluoromethyl)oxirane and Their Gas-Phase Heterodimers with the Argon Atom.

The cis and trans isomers of the chiral tagging candidate molecule, 2-fluoro-3-(trifluoromethyl)oxirane, as well as the lowest energy gas-phase heterodimer of each with the argon atom, are characterized via quantum chemistry calculations and microwave rotational spectroscopy from 5 to 18 GHz and their ground state, vibrationally averaged structures, are determined. Apart from the cis/trans nature of the ring substitution and small differences in the dihedral angle specifying the rotation of the trifluoromethyl group, the two oxirane molecules and their respective argon complexes each have remarkable structural similarity. In contrast, the binding mode of argon to the oxirane, while similar for the two complexes here, is distinct from those modes observed in previous argon-fluorooxirane species. The ability to tune the preferred mode of binding with differing levels of fluorine substitution may prove advantageous in applications of chiral tagging to a wide variety of analytes.

Synthesis, in vitro anticancer activity, and pharmacokinetic profiling of the new tetrahydropyrimidines:Part I.

Different vanillin-based aldehydes were used to synthesize novel tetrahydropyrimidines (THPMs) via conventional Biginelli reaction. The THPMs were tested against human normal cells (MRC-5) and cancer cell lines (HeLa, K562, and MDA-MB-231). With IC50 values of 10.65, 10.70, and 12.76 µM, compounds 4g, 4h, and 4i exerted the strongest cytotoxic effects against K562 cells. The best activity was achieved for 4g on MDA-MB-231 cells (IC50 = 9.20 ± 0.14 µM). The effects of compounds 4g, 4h, and 4i on the cell-cycle phase distribution of K562 cells were analyzed. Principal component analysis was carried out for the chemometrics analysis to comprehend the relationship between the anticancer activity of the THPMs, pharmacokinetic properties, and partition coefficients, as well as the relationship between the chromatographic behavior and retention parameters. The highest retention rates are found for molecules 4g, 4h, and 4i, which have the longest carbon chains, indicating that the length of the alkyl chain positively affects the molecule's anticancer activity but only if the number of carbon atoms is not higher than seven. Additionally, molecular docking analysis was performed to determine the preferred binding modes of the investigated ligands (4g, 4h, and 4i) with a DNA dodecamer and bovine serum albumin.

Easy and Effective Method for α-CD:N2O Host-Guest Complex Formation.

α-CD:N2O "host-guest" type complexes were formed by a simple solid-gas reaction (N2O sorption into α-CD) under different gas pressures and temperatures. The new N2O inclusion method applied in the present study was compared with the already known technique based on the crystallization of clathrates from a water solution of α-CD saturated with N2O. A maximum storage capacity of 4.5 wt.% N2O was achieved when charging the cyclodextrin from a gas phase. The amount of included gas decreases to 1.3 wt.% when the complex is stored in air at 1 atm and room temperature, analogous to that achieved by the crystallization of α-CD:N2O. Furthermore, it was shown that the external coordination of N2O to either the upper or lower rim of α-CD without hydration water displacement is the preferred mode of binding, due to hydrogen bonds with neighboring -OH groups from the host macrocycle and three of the hydration water molecules nearby. The capacity of α-CD to store N2O and the thermal stability of the α-CD:N2O complex demonstrated promising applications of these types of complexes in food and beverages.

Interaction with CT-DNA and in vitro cytotoxicity of two new copper(II)-based potential drugs derived from octanoic hydrazide ligands

Two copper(II) complexes [Cu(Hpmoh)(NO3)(NCS)] (1) and [Cu(peoh)(N3)]2 (2) were designed and synthesized by reaction of Cu(NO3)2·3H2O with hydrazone Schiff base ligands,abbreviated with Hpmoh and Hpeoh. Hpmoh and Hpeoh were prepared by condensation reaction of octanoic hydrazide with pyridine-2-carboxyaldehyde and 2-acetylpyridine, respectively. Complexes 1 and 2 were characterized using different analytical techniques such as FT-IR, UV–Vis, IR, EPR and single X-ray diffraction (XRD) analyses as well as computational methods (DFT). The XRD of 1 and 2 shows a mononuclear or a dinuclear structure with the copper(II) centre adopting a slightly distorted square pyramidal geometry. In water-containing solution and in DMSO, 1 and 2 undergo a partial transformation with formation of [Cu(Hpmoh)(NO3)(NCS)] (1) and [Cu(Hpmoh)(NO3)(H2O/DMSO)] (1a) in one system and [Cu(peoh)(N3)] (2a) in the other one, as supported by DFT calculations. Docking simulations confirmed that the intercalation is the preferred binding mode with DNA for 1, 1a and 2a, but suggested that the minor groove binding is also possible. A significant fluorescence quenching of the DNA–ethidium bromide conjugate was observed upon the addition of complexes 1 and 2 with a quenching constant around 104 M−1 s−1. Finally, both 1 and 2 were examined for anti-cancer activity using MDA-MB-231 (human breast adenocarcinoma) and A375 (malignant melanoma) cell lines through in vitro MTT assay which suggest comparable cancer cell killing efficacy, with the higher effectiveness of 2 due to the dissociation into two [Cu(peoh)(N3)] units.

Biocatalytic Regioselective O-acylation of Sesquiterpene Lactones from Chicory: A Pathway to Novel Ester Derivatives.

We report the first biocatalytic modification of sesquiterpene lactones (STLs) found in the chicory plants, specifically lactucin (Lc), 11β,13-dihydrolactucin (DHLc), lactucopicrin (Lp), and 11β,13-dihydrolactucopicrin (DHLp). The selective O-acylation of their primary alcohol group was carried out by the lipase B from Candida antarctica (CAL-B) using various aliphatic vinyl esters as acyl donors. Perillyl alcohol, a simpler monoterpenoid, served as a model to set up the desired O-acetylation reaction by comparing the use of acetic acid and vinyl acetate as acyl donors. Similar conditions were then applied to DHLc, where five novel ester chains were selectively introduced onto the primary alcohol group, with conversions going from >99 % (acetate and propionate) to 69 % (octanoate). The synthesis of the corresponding O-acetyl esters of Lc, Lp, and DHLp was also successfully achieved with near-quantitative conversion. Molecular docking simulations were then performed to elucidate the preferred enzyme-substrate binding modes in the acylation reactions with STLs, as well as to understand their interactions with crucial amino acid residues at the active site. Our methodology enables the selective O-acylation of the primary alcohol group in four different STLs, offering possibilities for synthesizing novel derivatives with significant potential applications in pharmaceuticals or as biocontrol agents.

Simultaneous Hydrogen Bonds with Different Binding Modes: The Acceptor “Rules” but the Donor “Chooses”

Invited for the cover of this issue is the group of Cristina Trujillo at Trinity College Dublin and the University of Manchester. The image depicts a market run by hydrogen bond acceptors in which hydrogen-bond-donor "customers" are choosing their preferred binding mode "vegetable". Read the full text of the article at 10.1002/chem.202203577.

Anti‐Diabetic Activity of Flavonol Glucosides From Fumana montana Pomel: In vitro Analysis, In Silico Docking, ADMET Prediction, and Molecular Dynamics Simulations

AbstractOne of the major challenges in type 2 diabetes is the inhibition of the enzyme alpha‐amylase, since many molecules targeting this enzyme based on or derived from medicinal plants have been synthesized to counteract the α‐amylase action. The present study investigated the in‐vitro and in‐silico antidiabetic capacities of three flavonol glucosides obtained from the plant Fumana montana Pomel using α‐amylase inhibition model. α‐amylase binding interaction with the studied compounds was examined using ultraviolet‐visible absorption spectroscopy technique. Molecular docking and ADMET prediction were also performed for the three phytoconstituents towards human pancreatic alpha‐amylase receptor. The in vitro results revealed that both compound FG1 and FG3 showed a higher antidiabetic activity (84.00±0.12 and 85.36±0.12 μg/ml respectively) than that of standard antidiabetic acarbose (91.12±0.11). The value of the binding free energy ranging from −31.66±0.07 to −32.68±0.03 KJ mol−1 demonstrated the spontaneity and the strong binding betweenα‐amylase and the studied phytoconstituents. Molecular docking study indicated the preferred binding site and binding mode, and further suggested that the binding mode of the three compounds to the target enzyme is of hydrogen bonding and hydrophobic forces. Further analysis by molecular dynamic simulation studies showed that FG2 was stable in the HPA active site. In vitro and in‐silico results showed that the studied phytoconstituents interacted with α‐amylase and their binding interaction resulted in reduction of the enzyme's activity.

Structural predictions of protein-DNA binding: MELD-DNA.

Structural, regulatory and enzymatic proteins interact with DNA to maintain a healthy and functional genome. Yet, our structural understanding of how proteins interact with DNA is limited. We present MELD-DNA, a novel computational approach to predict the structures of protein-DNA complexes. The method combines molecular dynamics simulations with general knowledge or experimental information through Bayesian inference. The physical model is sensitive to sequence-dependent properties and conformational changes required for binding, while information accelerates sampling of bound conformations. MELD-DNA can: (i) sample multiple binding modes; (ii) identify the preferred binding mode from the ensembles; and (iii) provide qualitative binding preferences between DNA sequences. We first assess performance on a dataset of 15 protein-DNA complexes and compare it with state-of-the-art methodologies. Furthermore, for three selected complexes, we show sequence dependence effects of binding in MELD predictions. We expect that the results presented herein, together with the freely available software, will impact structural biology (by complementing DNA structural databases) and molecular recognition (by bringing new insights into aspects governing protein-DNA interactions).

New Insights into the Role of Ligand-Binding Modes in GC-DNA Condensation through Thermodynamic and Spectroscopic Studies.

In biological systems, the unprompted assembly of DNA molecules by cationic ligands into condensed structures is ubiquitous. The ability of ligands to provoke DNA packaging is crucial to the molecular organization and functional control of DNA, yet their underlined physical roles have remained elusive. Here, we have examined the DNA condensation mechanism of four cationic ligands, including their primary DNA-binding modes through extensive biophysical studies. We observed contrasting changes for these ligands binding to poly[dGdC]:poly[dGdC] (GC-DNA) and poly[dAdT]:poly[dAdT] (AT-DNA). Based on a CD spectroscopic study, it was confirmed that only GC-DNA undergoes B- to Ψ-type DNA transformation in the presence of ligands. In the fluorescence displacement assay (FDA), the ability of ligands to displace GC-DNA-bound EtBr follows the order: protamine21+ > cohex3+ > Ni2+ > spermine4+, which indicates that there is no direct correlation between the ligand charge and its ability to displace the drug from the DNA, indicating that GC-DNA condensation is not just influenced by electrostatic interaction but ligand-specific interactions may also have played a crucial role. Furthermore, the detailed ITC-binding studies suggested that DNA-ligand interactions are generally driven by unfavorable enthalpy and favorable entropy. The correlations from various studies insinuate that cationic ligands show major groove binding as one of the preferred binding modes during GC-DNA condensation.

Immobilization of Biantennary N-Glycans Leads to Branch Specific Epitope Recognition by LSECtin.

The molecular recognition features of LSECtin toward asymmetric N-glycans have been scrutinized by NMR and compared to those occurring in glycan microarrays. A pair of positional glycan isomers (LDN3 and LDN6), a nonelongated GlcNAc4Man3 N-glycan (G0), and the minimum binding epitope (the GlcNAcβ1-2Man disaccharide) have been used to shed light on the preferred binding modes under both experimental conditions. Strikingly, both asymmetric LDN3 and LDN6 N-glycans are recognized by LSECtin with similar affinities in solution, in sharp contrast to the results obtained when those glycans are presented on microarrays, where only LDN6 was efficiently recognized by the lectin. Thus, different results can be obtained using different experimental approaches, pointing out the tremendous difficulty of translating in vitro results to the in vivo environment.

Inclusion complexation of emodin with various β-cyclodextrin derivatives: Preparation, characterization, molecular docking, and anticancer activity

Encapsulation with β-cyclodextrin (βCD) has primarily been used to enhance the solubility of lipophilic guest molecules. Emodin (ED) stands out for its profound biological properties, especially anticancer activity. However, its usage in pharmaceutical applications has been hindered by its poor aqueous solubility. In the present work, we performed inclusion complexation of ED with βCD and its derivatives: hydroxypropyl-β-cyclodextrin (HPβCD), sulfobutylether-β-cyclodextrin with degree of substitution (DS) of 2 (SBE2βCD) and 6.0–7.1 (SBE7βCD) and 2,6-di-O-methyl-β-cyclodextrin (DMβCD), to identify the most promising drug carrier to enhance the water solubility and the anticancer activity of ED. The AL-type phase solubility diagram indicates 1:1 stoichiometry between ED and βCDs. The ED/DMβCD complex shows the highest stability (KC = 3800 M−1) and the highest water solubility (113.86 µg/mL) at 30 °C, followed by ED/SBE7βCD, ED/HPβCD, ED/SBE2βCD, and ED/βCD complexes. The SEM micrographs and DSC thermograms confirmed the inclusion complex formation between host and guest by attaining new surface morphological structures and thermal behaviors, respectively. Molecular docking suggests C-form insertion as the preferred binding mode of ED toward βCDs. Interestingly, the anti-proliferative effect on KKU-213A, KKU-213B, A549, and H1975 cancer cell lines of inclusion complexes, especially ED/DMβCD, ED/SBE7βCD, and ED/HPβCD, was significantly higher than that of ED alone.

Design, synthesis and spectroscopic and structural characterization of novel N-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology.

The novel compound N-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide, C16H17NO4, I, was prepared by a two-step reaction and then characterized by elemental analysis and X-ray diffraction (XRD) methods. Moreover, its spectroscopic properties were investigated by FT-IR and 1H and 13C NMR. Compound I crystallized in the monoclinic space group P21/c and the molecular geometry is not planar, being divided into three planar regions. Supramolecular structures are formed by connecting units via hydrogen bonds. The ground-state molecular structure of I was optimized by the DFT-B3LYP/6-31G(d,p) method and the theoretical structure was compared with that obtained by X-ray diffraction. Intermolecular interactions in the crystal network were studied by two-dimensional (2D) and three-dimensional (3D) Hirshfeld analyses. The calculated electronic transition results were examined and the molecular electrostatic potentials (MEPs) were also determined. The in vitro antimicrobial activities of I against three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined. The compound was compared with several control drugs and showed better activity than the amoxicillin standard against Gram-positive bacteria B. subtilis, S. aureus and E. faecalis, and Gram-negative bacteria E. coli, K. pneumoniae and P. aeruginosa. The density functional theory (DFT)-optimized structure of the small molecule was used to perform molecular docking studies with proteins from experimentally studied bacterial and fungal organisms using AutoDock to determine the most preferred binding mode of the ligand within the protein cavity. A druglikeness assay and ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out and predict a good drug-like character.

Synthesis, spectroscopic characterization, biological activities, X-ray diffraction and molecular docking studies of 2-methyl-3-(thiazol-2-ylcarbamoyl)phenylacetate

We performed a different methodology for amide bond formation, the 2-methyl-3-(thiazol-2-ylcarbamoyl)phenylacetate (MTP) compound, which was prepared from the reaction of 3-acetoxy-2-methylbenzoic anhydride with thiazol-2-amine. The MTP compound was characterized with the assistance of various spectral techniques including IR, 1H NMR, 13C NMR, XRD and elemental analysis. The MTP has been crystallized in the monoclinic space group P21/n. The ground state molecular structure (GSMS) of the optimized MTP was obtained using the DFT/B3LYP/6–31G(d,p) method. Then, intermolecular interactions for the MTP crystal were conducted by the 2D and 3D Hirshfeld analyses. Next, the DFT-optimized structure of MTP compound was used to perform molecular docking studies with the proteins of bacterial and fungal organisms in order to find the most preferred binding mode of ligand within the protein cavity. Druglikeness assay, ADME and Toxicology studies have been carried out to predict whether the MTP has an effective drug characteristics or not. The antimicrobial activity of the MTP was tested in terms of antibacterial and antifungal activities. The results revealed that this MTP showed the best activity against B. licheniformis among four bacterial species and A. flavus and C. utilis among five fungal species. These findings indicate that this and similar compounds with thiazole ring can be used as antibacterial agents in the future.

Co-Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenström Macroglobulinemia Lymphoma.

In recent times, the development of combination therapy has been a focal point in drug discovery. This article explores the potential synergistic effect of co-administration of Bcl2 inhibitor Venetoclax and BET inhibitor JQ1. We envisioned that the 'dual-site'-binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenström macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co-binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed - Venetoclax increased the binding affinity of JQ1 by 11.5 %, while JQ1 boosted the binding affinity of Venetoclax by 16.3 % when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.

A reusable and sensitive electrochemical sensor for determination of Allura red in the presence of Tartrazine based on functionalized nanodiamond@SiO2@TiO2; an electrochemical and molecular docking investigation

A sensitive and novel electrochemical sensor for the detection of Allura Red (AR) in the presence of tartrazine (TRZ) was fabricated using a screen-printed electrode modified by functionalized nanodiamond covered using silicon dioxide and titanium dioxide nanoparticles (F-nanodiamond@SiO2@TiO2/SPE). Scanning electron microscopy (SEM), brunauer–Emmett–teller (BET), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR) techniques were performed to characterize the as-synthesized Fnanodiamond@SiO2@TiO2 nanocomposite. The as-fabricated electrode demonstrated two wide dynamic ranges of 0.01–0.12 and 0.12–8.65 μM with a limit of detection (LOD) as low as 1.22 nM. Moreover, the modified electrode exhibits excellent repeatability, reproducibility, reusability, selectivity, and stability with high sensitivity of 44.3 μA μM−1 cm−1, offering good prospects in the simple, cost-effective, and rapid assessment of their total concentration. The successful detection of AR and TRZ, simultaneously and individually in food samples, revealed the applicability of the sensor in the determination of AR and TRZ with satisfactory recovery. Therefore, these advantages provide an excellent possibility for the smart monitoring of AR and TRZ in the future. In the final step, the preferential intercalative binding mode of Allura red with ds-DNA was approved for the first time by a molecular docking study. This study paves the way for engineering highly sensitive DNA biosensors to monitor azo dye compounds by combining the benefits of nanocomposites and valuable information of a molecular docking study.

Multi-catalytic Sites Inhibition of Bcl2 Induces Expanding of Hydrophobic Groove: A New Avenue Towards Waldenström Macroglobulinemia Therapy.

B-cell lymphoma 2 (Bcl2) is a key protein regulator of apoptosis. The hydrophobic groove in Bcl2 is a unique structural feature to this class of enzymes and found to have a profound impact on protein overall structure, function, and dynamics. Dynamics of the hydrophobic groove is an essential determinant of the catalytic activity of Bcl2, an implicated protein in Waldenström macroglobulinemia (WM). The mobility of α3-α4 helices around the catalytic site of the protein remains crucial to its activity. The preferential binding mechanisms of the multi-catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. In addition to our previous report on the same protein, herein, we further investigate the preferential binding modes and the conformational implications of Venetoclax-JQ1 dual drug binding at both catalytic active sites of Bcl2. Structural analysis revealed asymmetric α3-α4 helices movement with the expansion of the distance between the α3 and α4 helix in Venetoclax-JQ1 dual inhibition by 15.2% and 26.3%, respectively when compared to JQ1 and Venetoclax individual drug inhibition-resulting in remarkable widening of hydrophobic groove. Moreso, a reciprocal enhanced binding effect was observed: Venetoclax increased the binding affinity of JQ1 by 11.5%, while the JQ1 fostered the binding affinity of Venetoclax by 16.3% compared with individual inhibition of each drug. This divergence has also resulted in higher protein stability, and prominent correlated motions were observed with the least fluctuations and multiple van der Waals interactions. Findings offer vital conformational dynamics and structural mechanisms of enzyme-single ligand and enzyme-dual ligand interactions, which could potentially shift the current therapeutic protocol of Waldenström macroglobulinemia.

Comprehensive investigation of binding of some polycyclic aromatic hydrocarbons with bovine serum albumin: Spectroscopic and molecular docking studies

The interactions of phenanthrene (PHTN), fluorene (FLRN) and fluoranthene (FLRT) as polycyclic aromatic hydrocarbons (PAHs) with bovine serum albumin (BSA) were explored employing spectroscopic approaches and molecular docking simulations. Based on fluorescence quenching analysis FLRT showed higher binding affinity to BSA comparing with PHTN and FLRN. PHTN/FLRN/FLRT quenched the intrinsic fluorescence of BSA in the form of the mixed mechanism. Synchronous fluorescence spectroscopy, UV–Vis and circular dichroism spectroscopy demonstrated that presence of PHTN/FLRN/FLRT induced conformational alterations in BSA molecules. Based on the Förster resonance energy transfer (FRET) theory, the binding distances between the donor (BSA) and the acceptor (PHTN/FLRN/FLRT) were 3.85, 2.34 and 2.69 nm, respectively. Molecular docking simulations of 16 EPA priority PAHs were carried out to disclose their preferred binding modes. Docking analysis demonstrated that PAHs were bound to BSA stronger as the number of aromatic rings increased. Moreover, the results revealed the role of differences in the location of aromatic rings in PAHs on their interactions with BSA despite equivalent number of aromatic rings. Van der Waals forces dominated the formation of the.BSA-PAHs complexes. Most studied PAHs were bound to the IIIB region of BSA; however, the sterically bulky PAHs like benzo[g,h,i]perylen and indeno[1,2,3cd]pyrene were located in the IIIA and IIB regions of BSA. Naproxen, the co-crystalized ligand, was redocked to the crystal structure of BSA and root mean square deviation value was found to be 1.96 Å highlighting the predictive accuracy of the docking protocol.

A synergistic multitargeted of BET and HDAC: an intra-molecular mechanism of communication in treatment of Waldenström macroglobulinemia

ABSTRACT Preclinical evidence suggests effectiveness of the combined inhibition of bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) proteins in the treatment of Waldenström macroglobulinemia (WM). However, toxicity, dosing scheduling, and drug–drug interactions are common challenges in combined therapy. In this article, we scrutinise the potential synergistic effect of a dual acting anti-cancer therapy using a single drug TW22 that concomitantly inhibits BET/HDAC proteins, which may open a new line of therapeutic protocol in the treatment of Waldenström macroglobulinemia (WM). The preferential binding mechanisms of the dual inhibition of BET/HDAC enzymes have been a subject of debate in literature. In this report, molecular dynamic simulations coupled with other advanced biocomputational tools were applied to investigate the preferential binding modes and the conformational implications of dual inhibition of both BET/HDAC enzymes. Intriguingly, findings show that multitarget TW22 have superior binding affinity by16.2% and 39.8% than BET/HDAC parent inhibitor molecules JQ1 and Panobinostat, respectively. This disparity has also resulted in higher protein stability and prominent correlated motions were observed with the least fluctuations and multiple van der Waals interactions. The findings of this study will aid in the design of improved anti-cancer agents, thus allowing for increased patient adherence.