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BACKGROUND RESULTS CONCLUSION Mycotoxin contamination of food has been gaining increasing attention. Hidden mycotoxins that interact with biological macromolecules in food could make the detection of mycotoxins less accurate, potentially leading to the underestimation of the total exposure risk. Interactions of the mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) with high‐molecular glutenin were explored in this study.The recovery rates of AOH and AME (1, 2, and 10 μg kg−1) in three types of grains (rice, corn, and wheat) were relatively low. Molecular dynamics (MD) simulations indicated that AOH and AME bound to glutenin spontaneously. Hydrogen bonds and π‐π stacking were the primary interaction forces at the binding sites. Alternariol with one additional hydroxyl group exhibited stronger binding affinity to glutenin than AME when analyzing average local ionization energy. The average interaction energy between AOH and glutenin was −80.68 KJ mol−1, whereas that of AME was −67.11 KJ mol−1.This study revealed the mechanisms of the interactions between AOH (or AME) and high‐molecular glutenin using MD and molecular docking. This could be useful in the development of effective methods to detect pollution levels. These results could also play an important role in the evaluation of the toxicological properties of bound altertoxins. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Context: The interface of Hsp70-Bim protein–protein interaction (PPI) has been identified as a specific target for Chronic Myeloid Leukemia (CML) therapy and the specific inhibitors were developed to exhibit in vivo anti-leukemia activities. Herein, we explored the binding mechanism of a Hsp70-Bim inhibitor, 6-(cyclohexylthio)-3-((2-morpholinoethyl) amino)-1-oxo-1H-phenalene-2-carbonitrile (S1g-6), to Hsp70 at the atomic level by MD simulation. TYR-149, THR-222, ALA-223, and GLY-224 on Hsp70 were identified as four key residues that contribute to Hsp70/S1g-6 complex. Moreover, the site mutation validation demonstrated the TYR-149 of Hsp70 is a "hot-spot" in the Hsp70-Bim PPI interface. These results could benefit the design of further inhibitors to occupy the Bim binding site on the Hsp70 surface. Methods: The binding mechanism of S1g-6 and Hsp70 was predicted through the molecular dynamics (MD) method by Gromacs-2021.3. The MD simulation was performed with 100-ps NVT and 100-ps NPT ensemble, and the force field was chosen as the Charmm36 force field. The temperature was set as 300 K, the time step was 2 fs and the total MD simulation time was 500 ns. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a public health concern, especially in Brazil and India. The drugs available for therapy are old, cause toxicity and have reports of resistance. Therefore, this paper aimed to carry out initial structure-activity relationships (applying molecular docking and dynamic simulations) of arylindole scaffolds against the pteridine reductase (PTR1), which is essential target for the survival of the parasite. Thus, we used a series of 43 arylindole derivatives as a privileged skeleton, which have been evaluated previously for different biological actions. Compound 7 stood out among its analogues presenting the best results of average number of interactions with binding site (2.00) and catalytic triad (1.00). Additionally, the same compound presented the best binding free energy (−32.33 kcal/mol) in dynamic simulations. Furthermore, with computational studies, it was possible to comprehend and discuss the influences of the substituent sizes, positions of substitutions in the aromatic ring and electronic influences. Therefore, this study can be a starting point for the structural improvements needed to obtain a good leishmanicidal drug. [ABSTRACT FROM AUTHOR]

In this work, we report a novel method for the label-free detection of cyanotoxin molecules based on a direct assay utilizing a graphene-modified surface plasmon resonance (SPR) aptasensor. Molecular dynamic simulation of the aptamer's interaction with cylindrospermopsin (CYN) reveals the strongest binding sites between C18–C26 pairs. To modify the SPR sensor, the wet transfer method of CVD monolayer graphene was used. For the first time, we report the use of graphene functionalized by an aptamer as a bioreceptor in conjunction with SPR for the detection of CYN. In a direct assay with an anti-CYN aptamer, we demonstrated a noticeable change in the optical signal in response to the concentrations far below the maximum tolerable level of 1 µg/L and high specificity. [ABSTRACT FROM AUTHOR]

In the present study, new structural variants of 4-hydroxyquinolinone-hydrazones were designed and synthesized. The structure elucidation of the synthetic derivatives 6a–o was carried out using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, and elemental analysis, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 6a–o exhibited good α-glucosidase inhibition with IC50 values ranging between 93.5 ± 0.6 to 575.6 ± 0.4 µM as compared to the standard acarbose (IC50 = 752.0 ± 2.0 µM). Structure–activity relationships of this series were established which is mainly based on the position and nature of the substituent on the benzylidene ring. A kinetic study of the active compounds 6l and 6m as the most potent derivatives were also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of the enzyme were determined by molecular docking and molecular dynamic simulations. [ABSTRACT FROM AUTHOR]

Plasmodium vivax (P. vivax) is one of the human's most common malaria parasites. P. vivax is exceedingly difficult to control and eliminate due to the existence of extravascular reservoirs and recurring infections from latent liver stages. Traditionally, licorice compounds have been widely investigated against viral and infectious diseases and exhibit some promising results to combat these diseases. In the present study, computational approaches are utilized to study the effect of licorice compounds against P. vivax Duffy binding protein (DBP) to inhibit the malarial invasion to human red blood cells (RBCs). The main focus is to block the DBP binding site to Duffy antigen receptor chemokines (DARC) of RBC to restrict the formation of the DBP–DARC complex. A molecular docking study was performed to analyze the interaction of licorice compounds with the DARC binding site of DBP. Furthermore, the triplicates of molecular dynamic simulation studies for 100 ns were carried out to study the stability of representative docked complexes. The leading compounds such as licochalcone A, echinatin, and licochalcone B manifest competitive results against DBP. The blockage of the active region of DBP resulting from these compounds was maintained throughout the triplicates of 100 ns molecular dynamic (MD) simulation, maintaining stable hydrogen bond formation with the active site residues of DBP. Therefore, the present study suggests that licorice compounds might be good candidates for novel agents against DBP-mediated RBC invasion of P. vivax. [ABSTRACT FROM AUTHOR]

One 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. [ABSTRACT FROM AUTHOR]

To identify potent urease inhibitors, in the current study, a series of thioxothiazolidinyl-acetamides were designed and synthesized. The prepared compounds were characterized by spectroscopic techniques, including FTIR, 1HNMR, 13CNMR, and elemental analysis. In the enzymatic assessments, it was demonstrated that all derivatives had significant urease inhibition with IC50 values in the range of 1.473–9.274 µM in comparison with the positive control hydroxyurea (IC50 = 100.21 ± 2.5 µM) and thiourea (IC50 = 23.62 ± 0.84 µM). Compound 6i (N-benzyl-3-butyl-4-oxo-2-thioxothiazolidine-5-carboxamide) was the most active agent with an IC50 value of 1.473 µM. Additionally, kinetic investigation and in silico assessments of 6i was carried out to understand the type of inhibition and behavior of the most potent derivative within the binding site of the enzyme. Noteworthy, the anti-urease assay against P. vulgaris revealed 6e and 6i as the most active agents with IC50 values of 15.27 ± 2.40 and 17.78 ± 3.75 µg/mL, respectively. Antimicrobial evaluations of all compounds reveal that compounds 6n and 6o were the most potent antimicrobial agents against the standard and resistant S. aureus. 6n and 6o also showed 37 and 27% inhibition in the development of biofilm by S. aureus at 512 µg/ml. Furthermore, the MTT test showed no toxicity up to 100 µM. Taken together, the study suggests that the synthesized thioxothiazolidinyl-acetamides bases derivatives may serve as potential hits as urease inhibitors. [ABSTRACT FROM AUTHOR]

Context: Egypt has a high prevalence of the hepatitis C virus (HCV) genotype 4a (GT-4a). Unfortunately, the high resistance it exhibited still was not given the deserved attention in the scientific community. There is currently no consensus on the NS5A binding site because the crystal structure of HCV NS5A has not been resolved. The prediction of the binding modes of direct-acting antivirals (DAA) with the NS5A is a point of controversy due to the fact that several research groups presented different interaction models to elucidate the NS5A binding site. Consequently, a 3D model of HCV NS5A GT-4a was constructed and evaluated using molecular dynamics (MD) simulations. The generated model implies an intriguing new orientation of the AH relative to domain I. Additionally, the probable binding modes of marketed NS5A inhibitors were explored. MD simulations validated the stability of the predicted protein–ligand complexes. The suggested model predicts that daclatasvir and similar drugs bind symmetrically to HCV NS5A GT-4a. This will allow for the development of new NS5A-directed drugs, which may result in reduced resistance and/or a wider range of effectiveness against HCV. Methods: The 3D model of HCV NS5A GT-4a was constructed using the comparative modeling approach of the web-based application Robetta. Its stability was tested with 200-ns MD simulations using the Desmond package of Schrodinger. The OPLS2005 force field was assigned for minimization, and the RMSD, RMSF, and rGyr were tracked throughout the MD simulations. Fpocket was used to identify druggable protein pockets (cavities) over the simulation trajectories. The binding modes of marketed NS5A inhibitors were then generated and refined with the aid of docking predictions made by FRED and AutoDock Vina. The stability of these drugs in complex with GT-4a was investigated by using energetic and structural analyses over MD simulations. The Prime MM-GBSA (molecular mechanics/generalized Born surface area) method was used as a validation tool after the docking stage and for the averaged clusters after the MD simulation stage. We utilized PyMOL and VMD to visualize the data. [ABSTRACT FROM AUTHOR]

The primary focus of bisphosphonate medications is on targeting human farnesyl pyrophosphate synthase (hFPPS), an essential regulator of mammalian isoprenoids. Yet, these drugs encounter limitations due to their restricted "druglike" properties and their effectiveness primarily in treating skeletal disorders. In this study, we synthesized novel non-bisphosphonate compounds, using 4,4'-(ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde) (1) as a starting compound, with the aim of targeting hFPPS through a mixed binding approach. Among the various compounds tested, compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC 50 values of 1.108 and 1.24 μM, respectively. Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. In an in vivo study conducted on ovariectomized rats, various biochemical markers including osteocalcin, estradiol, osteoprotegerin, bone mineral content, and density were negatively impacted, while levels of bone specific alkaline phosphatase, receptor activator of nuclear factor kappa-Β ligand, serum/urinary calcium, and phosphate increased. Notably, compound 4a exhibited antiresorptive properties similar to zoledronate, effectively restoring most of the perturbed biochemical estimations. These findings suggest the potential of compound 4a , a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis. [Display omitted] • Synthesis of novel non-bisphosphonate compounds targeting hFPPS through a mixed binding approach. • Compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC 50 values of 1.108 and 1.24 μM, respectively. • Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. • Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. • In vivo studies, compound 4a exhibited antiresorptive properties similar to zoledronate, the findings suggest that compound 4a is a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis. [ABSTRACT FROM AUTHOR]

Enzymes are one of the most important biological molecules in organisms. Systematic study of the functions of enzymes is of great value to scientific research and industrial application. In recent years, the methods of enzyme function prediction based on computer technology have been developing and improving. Based on this context, this paper summarizes the main computational-based methods of enzyme function prediction, including the binding sites, molecular docking, dynamic simulation, and molecular design. Meanwhile, the developing trend is discussed and prospected in this paper. [ABSTRACT FROM AUTHOR]

Many GTPases have been shown to utilize ATP too as the phosphoryl donor. Both GTP and ATP are important molecules in the cellular environments and play multiple and discrete functional role within the cells. In our present study, we showed that one of the purine metabolic enzymes Adenylosuccinate synthetase from Leishmania donovani (LdAdSS) which belongs to the BioD-superfamily of GTPases can also carry out the catalysis by hydrolysing ATP instead of its cognate substrate GTP albeit with less efficiency. Biochemical and biophysical studies indicated its ability to bind to ATP too but at a higher concentration of ATP compared to that of GTP. Sequence analysis and molecular dynamic simulations suggested that residues of the switch loop and the G4-G5 (593SAXD596) connected motif of LdAdSS plays a role in determining the nucleotide specificity. Though the crucial interaction between Asp596 and the nucleotide is broken when ATP is bound, interactions between the Ala594 and the adenine ring of ATP could still hold ATP in the GTP binding site. The results of the present study suggested that though LdAdSS is GTP specific, it still shows ATP hydrolysing activity. • Leishmania donovani Adenylosuccinate synthetase (LdAdSS), a GTPase can also utilize ATP for phosphoryl transfer onto IMP instead of GTP. • The binding affinity of LdAdSS with GTP is stronger than with ATP. • LdAdSS switch loop assumes a closed catalytically active conformation on GDP binding compared to the partially open conformation on ADP binding. • Residues belonging to the connected G4-G5 motif in LdAdSS may be a determinant of its purine base selectivity. [ABSTRACT FROM AUTHOR]

In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC50 values in the range of 40.6 ± 0.2–164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 10.0 μM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 μM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme. [ABSTRACT FROM AUTHOR]

Specifically targeting the With‐No‐Lysine (WNK1) kinase, which is implicated in hypertension, renders a significant challenge in discovering competitive inhibitors due to the highly conserved ATP‐binding pocket. However, an allosteric inhibitor may impart high specificity against the WNK kinase isoforms since it targets the less conserved site and can provide greater efficacy even under high physiological ATP concentration. In the current study, we have investigated the structural and energetic basis of the specificity of the allosteric inhibitor WNK476 against WNK kinase isoforms by combining molecular dynamics simulations and free energy calculations using molecular mechanics Poisson–Boltzmann surface area. Our study reveals that the conformational stabilization of αC‐helix near the allosteric binding site, including conformational changes in activation and glycine‐rich loop regions, favors the specificity of WNK476 toward WNK1. The MM/PBSA calculations suggest that the non‐polar contribution from hydrophobic residues and polar solvation energy influences WNK/WNK476 complexation. Despite more favorable electrostatic and van der Waals interactions in WNK2/WNK476, WNK476 is more potent against WNK1 due to the lower contribution of disfavoring components—polar solvation and entropy. Further, we have identified that the hydrophobic residues of DLG, αC‐helix, β4, and β5 regions, and H‐bond network near the β4 strand play a critical role in the specificity of WNK476 against WNK1. Finally, our study reveals that residues Leu272, Val281, Phe283, and Leu369 of WNK1 actively contribute to the overall hydrophobic interactions for WNK1/WNK476. Overall, our study might help in the rational design of novel allosteric inhibitors against hypertension. [ABSTRACT FROM AUTHOR]

The main mechanism for drug-drug interaction is displacement reaction of ligands from their protein binding sites. The aim of this study was to evaluate anticancer drug sorafenib displacement from the binding site on human serum albumin by commonly used plant flavonoids quercetin and rutin. The interaction between bio-macromolecules and drugs can also cause changes in protein structure and therefore was evaluated in this study by spectroscopic and molecular dynamic simulation techniques. Serum albumin, the main protein in the plasma acts in the disposition of many drugs and therefore, is a model protein for investigating drug/ligand binding and alteration in the spectrophotometric and molecular docking properties of drug/ligand. All the studied ligands sorafenib, quercetin and rutin bind to HSA with different binding affinity. The displacement of ligands from their binding sites was inferred from comparison of quenching and binding constants of binary and ternary systems. Conformational changes in the HSA were found with UV-spectroscopic, circular dichroism, FT-IR and three dimensional studies. The molecular dynamic simulation studies suggest a stable complex formation between HSA and sorafenib. Binding studies for HSA-sorafenib in presence of quercetin and rutin indicated displacement of sorafenib from its binding site. [ABSTRACT FROM AUTHOR]

A small collection of 2-hydroxy-N-(5-methyl/nonsubstituted 4-oxo-2-substituted phenyl-1,3-thiazolidin-3- yl)-2-phenylacetamides (3-16) was synthesized from the cyclocondensation of 2-hydroxy-2-phenyl-N'- [(substitutedphenyl)methylene]acetohydrazides (2) and mercaptoethanoic acid or 2-mercaptopropanoic acid, characterized with spectral and elemental analysis. In order to explore their antimycobacterial potential, newly synthesized fourteen compounds were screened for their inhibitory activity against Mycobacterium tuberculosis strain H37Rv at 6.25 µg/mL with in-vitro primary tests. Compound 7 was found to provide the highest inhibition (98%) M. tuberculosis strain H37Rv, while most of the new derivatives showed different inhibition ratios. For the search of the putative targets which are considered as related to the antimycobacterial activity of these molecules, docking studies were performed. With molecular dynamic simulations, further possible interactions between ligands and the active site of the selected enzymes were investigated. Eventually, molecular modelling studies indicated that at least part of the mechanism of action of these compounds may be mediated by inhibition of MtInhA. [ABSTRACT FROM AUTHOR]

The antibiotic resistance crisis is becoming dire, yet in the past several years few potential antibiotics or adjuvants with novel modes of action have been identified. The bacterial mechanosensitive channel of large conductance, MscL, found in the majority of bacterial species, including pathogens, normally functions as an emergency release valve, sensing membrane tension upon low-osmotic stress and discharging cytoplasmic solutes before cell lysis. Opening the huge ~30Å diameter pore of MscL inappropriately is detrimental to the cell, allowing solutes from and even passage of drugs into to cytoplasm. Thus, MscL is a potential novel drug target. However, there are no known natural agonists, and small compounds that modulate MscL activity are just now being identified. Here we describe a small compound, K05, that specifically modulates MscL activity and we compare results with those obtained for the recently characterized MscL agonist 011A. While the structure of K05 only vaguely resembles 011A, many of the findings, including the binding pocket, are similar. On the other hand, both in vivo and molecular dynamic simulations indicate that the two compounds modulate MscL activity in significantly different ways. [ABSTRACT FROM AUTHOR]

In this article, immobilized RNA aptamer on the gold nanoparticle surface was theoretically designed for selective detection of the neomycin B, neomycin C and paromomycin. Several molecular dynamic simulations on the pure aptamer, aptamer with –S(CH2)6– linker and immobilized aptamer on the gold nanoparticles surface were performed in the presence of different analytes. The obtained results indicate that the linker does not perturb the structure of the RNA aptamer. Also, full atomistic MD simulations on the immobilized RNA aptamer, as a biosensor, reveal a good sensing ability toward neomycin B in the presence of paromomycin and neomycin C. Due to complex formation, the distance of the aptamer and gold nanoparticles decreases. Moreover, the analysis of the electrostatic interactions between the aptamer and neomycin B shows a reduction in the tendency of the aptamer to interact with the gold nanoparticles, significantly. On the basis of the DFT-D3 calculations, neomycin B forms the most stable complex with the aptamer binding site, due to the strong hydrogen bond formation. Moreover, the obtained results indicate that electrostatic interactions are the driving forces of complex formation. On the basis of QM/MD results, the proposed aptasensor is a good candidate for the detection of neomycin B. [ABSTRACT FROM AUTHOR]

• Workflows of molecular docking and molecular dynamic simulation are overviewed. • Molecular docking reveals binding modes between myosin or myoglobin and additives. • Molecular dynamic simulation explores binding process of protein-additive complex. • Recent research of molecular methods in monitoring muscle quality is summarized. • Hydrogen and hydrophobic forces in protein-additive are proved by molecular methods. During storage and processing, muscle proteins, e.g. myosin and myoglobin, will inevitably undergo degeneration, which is thus accompanied by quality deterioration of muscle foods. Some exogenous additives have been widely used to interact with muscle proteins to stabilize the quality of muscle foods. Molecular docking and molecular dynamics simulation (MDS) are regarded as promising tools for recognizing dynamic molecular information at atomic level. Molecular docking and MDS can explore chemical bonds, specific binding sites, spatial structure changes, and binding energy between additives and muscle proteins. Development and workflow of molecular docking and MDS are systematically summarized in this review. Roles of molecular simulations are, for the first time, comprehensively discussed in recognizing the interaction details between muscle proteins and exogenous additives aimed for stabilizing color, texture, flavor, and other properties of muscle foods. Finally, research directions of molecular docking and MDS for improving the qualities of muscle foods are discussed. [ABSTRACT FROM AUTHOR]

Cas scaffolding protein family member 4 and protein tyrosine kinase 2 are signaling proteins, which are involved in neuritic plaques burden, neurofibrillary tangles, and disruption of synaptic connections in Alzheimer's disease. In the current study, a computational approach was employed to explore the active binding sites of Cas scaffolding protein family member 4 and protein tyrosine kinase 2 proteins and their significant role in the activation of downstream signaling pathways. Sequential and structural analyses were performed on Cas scaffolding protein family member 4 and protein tyrosine kinase 2 to identify their core active binding sites. Molecular docking servers were used to predict the common interacting residues in both Cas scaffolding protein family member 4 and protein tyrosine kinase 2 and their involvement in Alzheimer's disease-mediated pathways. Furthermore, the results from molecular dynamic simulation experiment show the stability of targeted proteins. In addition, the generated root mean square deviations and fluctuations, solvent-accessible surface area, and gyration graphs also depict their backbone stability and compactness, respectively. A better understanding of CAS and their interconnected protein signaling cascade may help provide a treatment for Alzheimer's disease. Further, Cas scaffolding protein family member 4 could be used as a novel target for the treatment of Alzheimer's disease by inhibiting the protein tyrosine kinase 2 pathway. [ABSTRACT FROM AUTHOR]

• A set of 1,2,3-triazolyl-based metronidazole hybrids (7a-m) was synthesized from the reaction of 2-methyl-5-nitro-1-(prop‑2-yn-1-yl)−1H-imidazole with β-azido alcohols in the presence of [CuL] as catalyst. • The in vitro cytotoxic activity of the synthesized compounds 7a-m were investigated against human melanoma cell line A375, using MTT assay. • Among all the synthesized compounds, compound 7l was found to be the most potent derivative with IC 50 value of 62.5 µM. • The molecular docking studies and molecular dynamic simulation were carried out to obtain the binding mode of these derivatives in the binding site of receptor. • This work is helpful for researchers who planning to design and develop anticancer agents. In the current study, a set of 1,2,3-triazolyl-based metronidazole hybrids (7a-m) was synthesized from the reaction of 2-methyl-5-nitro-1-(prop‑2-yn-1-yl)-1H-imidazole with β-azido alcohols in the presence of [CuL] as catalyst. The chemical structures of the synthesized compounds were characterized using different spectroscopic techniques (IR, 1H NMR, 13C NMR, Mass) and elemental analysis. Then, the in vitro cytotoxic activity of the synthesized compounds 7a-m were investigated against human melanoma cell line A375, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cytotoxic results showed that these compounds have moderate anticancer activity compared to methotrexate as a reference drug. Among all the synthesized compounds, compound 7l was found to be the most potent derivative with IC 50 value of 62.5 µM. Finally, the molecular docking studies and molecular dynamic simulation were carried out to obtain the binding mode of these derivatives in the binding site of receptor. The results of docking studies were in good agreement with the in vitro cytotoxic results. [Display omitted] [ABSTRACT FROM AUTHOR]

Interleukin-1β (IL1β) is a keynote mediator of inflammation with diverse physiological functions, playing a fundamental role in memory and mood regulation. The pleiotropic effects of IL-1β have been proposed to be implicated in the pathogenesis and etiology of depression. Thus, targeting IL-1β offers an inimitable opportunity to develop new strategies for an alternative therapy to treat depression. The focus of this study is to find out the potential inhibitors against IL-1β. Since, there is no oral specific drug reported yet thus, demanding an urgent need to develop new immunomodulatory drugs to combat chronic diseases. In this study, ligand-based pharmacophore modeling integrated with virtual screening and molecular docking strategy was designed to identify novel compounds capable of inhibiting the interactions towards cognitive receptor IL-1RI. In this connection, a set of 30,000 compounds were screened by a developed pharmacophore model that led to the retrieval of 2043 molecules from the in-house library and ZINC Database. Primarily, specific binding regions for IL-1β inhibitors have been explored by blind docking studies. After the selection of the binding site, the hits identified as actives based on the 3D-pharmacophore model were assessed by molecular docking studies. In a stepwise screening, six potential virtual hits were shortlisted for molecular dynamic simulation to acquire insights into their dynamic behavior. The obtained results highlighted that these compounds are stabilized in the targeted pocket of IL-1β and possibly block the formation of an active heterocomplex, subsequently locking the associated signaling cascade. Further in vitro experiments confirmed the inhibitory potential of Compound-157 and compound-283 with the IC 50 of 1.6 ± 0.1 and 9.1 ± 1.7 µg/mL respectively. [Display omitted] • The study encompasses of Ligand-Based pharmacophore modelling, docking simulation and mechanistic analysis. • Interfacial key residues were identified to design IL-1β/IL-1RI potential inhibitors. • The mechanistic results highlighted that shortlisted six virtual hits are stabilized in the targeted pocket of IL-1β and possibly block the formation of active heterocomplex. • IL-1β inhibitors are found in good agreement withexperimental studies. [ABSTRACT FROM AUTHOR]

The inhibition of α-amylase activity of the best component from Dalbergia odorifera was studied by virtual screening, spectroscopy analysis, molecular docking, and molecular dynamic simulation. [Display omitted] • Eriodictyol of Dalbergia odorifera is a crucial α-amylase inhibitor. • Eriodictyol quenched the intrinsic fluorescence of α-amylase by static quenching. • Eriodictyol binds to α-amylase and induces its conformation changes. • Eriodictyol interacts with α-amylase mostly driven by the hydrophobic interaction. Inhibiting the activity of α-amylase has been considered as one efficient way to prevent and treat type 2 diabetes recently. Dalbergia odorifera , a kind of Leguminosae plant, has a positive therapeutic effect on type 2 diabetes, possibly contributing by some constituents that can inhibit the activity of α-amylase. In this study, we found that eriodictyol was one potential constituent through virtual screening. The interaction mode between eriodictyol and α-amylase was elucidated by molecular docking, multi-spectroscopic analysis, and molecular dynamic simulation. The results revealed that eriodictyol quenched the intrinsic fluorescence of α-amylase, and the quenching mode was static quenching. Eriodictyol could spontaneously interact with α-amylase, mostly stabilized and influenced by the hydrophobic interaction, while the binding sites (n) was 1.13 ± 0.07 and binding constant (K b) was (1.43 ± 0.14) × 105 at 310 K, respectively. In addition, FT-IR and CD had been applied to identify that eriodictyol can trigger the conformational change of α-amylase. Taken together, the results provided some experimental data for developing new α-amylase inhibitors from Dalbergia odorifera , which may further prevent and treat diabetes and diabetes complications. [ABSTRACT FROM AUTHOR]

Flavonoids are a class of plant secondary metabolites that act as storage molecules, chemical messengers, as well as participate in homeostasis and defense processes. They possess pharmaceutical properties important for cancer treatment such as antioxidant and anti-tumor activities. The drug-related properties of flavonoids can be improved by glycosylation. The enzymes glycosyltransferases (GTs) glycosylate acceptor molecules in a regiospecific manner with the help of nucleotide sugar donor molecules. Several plant GTs have been characterized and their amino acid sequences determined. However, three-dimensional structures of only a few are reported. Here, phylogenetic analysis using amino acid sequences have identified a group of GTs with the same regiospecific activity. The structures of these closely related GTs were modeled using homologous GT structures. Their substrate binding sites were elaborated by docking flavonoid acceptor and UDP-sugar donor molecules in the modeled structures. Eight regions near the acceptor binding site in the N- and C- terminal domain of GTs have been identified that bind and specifically glycosylate the 3-OH group of acceptor flavonoids. Similarly, a conserved motif in the C-terminal domain is known to bind a sugar donor substrate. In certain GTs, the substitution of a specific glutamine by histidine in this domain changes the preference of sugar from glucose to galactose as a result of changed pattern of interactions. The molecular modeling, docking, and molecular dynamics simulation studies have revealed the chemical and topological features of the binding site and thus provided insights into the basis of acceptor and donor recognition by GTs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Quantum chemistry properties of ChEs inhibtors. [•] QSAR studies of ChEs inhibitors. [•] Configuration possibilities of AChE inhibitors. [•] Conformation changes of ChEs. [ABSTRACT FROM AUTHOR]

Abstract: The search for inhibitors of galactokinase (GALK) enzyme is interesting for their possible therapeutic application capable to alleviate symptoms in people with classic galactosemia. Several high-throughput screenings in the past have found candidate ligands showing a moderate affinity for GALK. Computational analysis of the binding mode of these compounds in comparison to their target protein has been performed only on crystallographic static structures, therefore missing the evolution of the complex during time. In this work, we applied static and dynamics simulations to analyze the interactions between GALK and its potential inhibitors, while taking into account the temporal evolution of the complexes. The collected data allowed us to identify the most important and persistent anchoring points of the known active site and of the newly identified secondary cavity. These data will be of use to increase the specificity and the affinity of a new generation of GALK inhibitors. [Copyright &y& Elsevier]

Abstract: Bacterial production of beta-lactamases, which hydrolyze beta-lactam type antibiotics, is a common antibiotic resistance mechanism. Antibiotic resistance is a high priority intervention area and one strategy to overcome resistance is to administer antibiotics with beta-lactamase inhibitors in the treatment of infectious diseases. Unfortunately, beta-lactamases are evolving at a rapid pace with new inhibitor resistant mutants emerging every day, driving the design and development of novel beta-lactamase inhibitors. Here, we examined the inhibitor recognition mechanism of two common beta-lactamases using molecular dynamics simulations. Binding of beta-lactamase inhibitor protein (BLIP) caused changes in the flexibility of regions away from the binding site. One of these regions was the H10 helix, which was previously identified to form a lid over an allosteric inhibitor binding site. Closer examination of the H10 helix using sequence and structure comparisons with other beta-lactamases revealed the presence of a highly conserved Trp229 residue, which forms a stacking interaction with two conserved proline residues. Molecular dynamics simulations on the Trp229Ala mutants of TEM-1 and SHV-1 resulted in decreased stability in the apo form, possibly due to loss of the stacking interaction as a result of the mutation. The mutant TEM-1 beta-lactamase had higher H10 fluctuations in the presence of BLIP, higher affinity to BLIP and higher cross-correlations with BLIP. Our results suggest that the H10 helix and specifically W229 are important modulators of the allosteric communication between the active site and the allosteric site. [Copyright &y& Elsevier]

[Display omitted] • Based on pharmacophore hybridization strategy, a novel series of quinazolinone-pyrazole derivatives were designed and synthesized. • All the title compounds displayed significant α-glucosidase inhibition with IC 50 values of 60.5 ± 0.3–186.6 ± 20 µM comparing with acarbose as the standard drug (IC 50 = 750.0 ± 10.0 µM). • Compound 9i was found to be the most active compound (IC 50 = 60.5 ± 0.3 µM). • Compound 9i was a competitive inhibitor against α-glucosidase (K i = 56 μM). • The molecular dynamic simulation and MM-GBSA calculation was performed to investigate the difference in structural perturbation and dynamic behavior. In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC 50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 μM) in comparison to standard acarbose (IC 50 = 750.0 ± 10.0 µM). Limited structure–activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 μM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme. [ABSTRACT FROM AUTHOR]

The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer's and Parkinson's, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson's treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sponges of the genus Echinoclathria are a source of cytotoxic sterols. • A new cytotoxic sterol, echinosterol with known one, thalassosterol were isolated. • Glucose-6-phosphate dehydrogenase inhibition and proliferation of cancer cells. • A comprehensive pharmacophore-based virtual screening was conducted. • Docking and molecular dynamic simulation studies. Chemical investigation of the methanol extract of the Red Sea sponge Echinoclathria sp., led to the isolation of two pure compounds, one new sterol, named as (echinosterol), compound (1), along with known first reported sterol, (thalassosterol), compound (2). Structure elucidation was achieved using different spectroscopic techniques. The in vitro cytotoxic activity of the isolated compounds was tested against three human cancer cell lines, MCF-7, HepG2, and HeLa. Both compounds displayed strong to moderate cytotoxicity with IC 50 values ranged from 3.23 to 28.1 µM. Subsequent pharmacophore-based virtual screening proposed glucose-6-phosphate dehydrogenase (G6PD) as the possible protein targets for both compounds, where they exhibited nanomolar inhibition (IC 50 14.59 ± 0.77 and 23.86 ± 1.25, and K i 15.3 ± 1.11 and 9.6 ± 1.2 µM, respectively) upon the in vitro testing. Docking and molecular dynamic simulation studies were further illustrated the binding modes of both compounds inside the enzyme's active site. [ABSTRACT FROM AUTHOR]

• Conserved H-bond of Asn_202 and 3b-OH groups stabilizes Abiratreone orientation. • D4,3-keto Abiraterone accepts H-bond from Arg-239, so show different H-bond pattern. • Van der Waals interactions dominate both heterocyclic inhibitors binding to CYP17A1. • Water molecules play crucial roles as competitors/accelerators in the H-bond network. The importance of computer-aided drug design and development is clear nowadays. These approaches smooth the way of designing some efficient candidates based on drugs in use. At this place, we studied the mechanism of D4-abiraterone (D4A), the active metabolite of Abiraterone (Abi), binding to CYP17A1 compared with Abi. The molecular dynamics simulation results reveal that the metabolite, which lacks the key 3β-OH group, has a varied H-bond forming pattern. The critical H-bond between 3β-OH of Abi with Asn_202 turns to 3 Keto-O of D4A with Arg_239 in the substrate-binding site. This interaction causes a remarkable distance of 0.63 nm between D4A nitrogen and Fe in heme, which reduces its 17,20 lyase selectivity. The D4A keto moiety presents an immense number of H-bond with surrounding solvent molecules compared with the Abi hydroxyl group. As a result, D4A develops a weaker H-bond network with the enzyme. Otherwise, the heterocyclic nature of inhibitors helps for noticeable van der Waals interaction formation with CYP17A1. However, Abi stabilized position in the binding site helps more van der Waals interactions deposition than D4A. These results convinced the importance of the conserved H-bond for acquiring the proper position by the substrate or inhibitor in the binding site. [ABSTRACT FROM AUTHOR]

1 Plasma protein binding has a major role in drug transportation and distribution. 2 Protein binding influences the pharmacokinetics and pharmacodynamics of drugs. 3 This study would be highly beneficial in the preclinical development of DHP 4 The study will provide information mechanism of binding forces and site involved while interacting with serum albumin. 5 In silico toxicity profile of DHP shows the drug to be safe for preclinical studies Human serum albumin (HSA) is the core protein in the systemic circulation and has a fundamental role in transportation and distribution of ligands in - vivo. In this study, a newly synthesized and patented anticancer dihydropyrimidine derivative; 4-(4-ethoxyphenyl)-5-(3,4,5- trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)-one (DHP) was evaluated for its binding to HSA. Ligand-HSA interaction is significant factor to attribute the toxicity or therapeutic potential to a ligand. Multi-spectroscopic studies combined with molecular modelling and molecular dynamic simulation (MDS) were conducted to understand the HSA-DHP binding mechanism. In-silico evaluation of DHP for its toxicity and metabolism was also conducted. Reduction in the binding constants was observed from 6.71 × 104 – 4.5 × 103 at increased temperatures which indicates moderate binding and the interaction was found to follow a static quenching mechanism. Further, Site I on HSA for DHP was established by competition with site specific markers and the results were supported by molecular docking. The stability of the HSA-DHP complex was established with MDS studies. Thermodynamics parameters revealed involvement of hydrogen bonding and van der Waals forces for HSA-DHP binding. An in-silico evaluation of DHP for its toxicity and metabolism provided that the synthesized compound was potentially safe and could be a promising candidate for further studies. Image, graphical abstract [ABSTRACT FROM AUTHOR]

A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease Mpro with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against Mpro crystal structure, these two compounds revealed a minimum binding energy of −8.87 and −8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CLpro) of SARS-CoV-2. Image 1 • Lymecycline and Mizolastine fit into Mpro binding substrate pocket with a binding energies of −8.87 kcal/mol and −8.71 kcal/mol, respectively. • ADMET analysis indicated drug-likeness properties of both Lymecycline and Mizolastine. • Molecular dynamic simulation and MM/PBSA binding free calculations showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. [ABSTRACT FROM AUTHOR]

• Zn2+ led cyclization makes protein rigid, protects active site against temperature. • H23 anchors Zn2+ ion and play key role in regulating structure-function properties. • H1 Zn2+ coordination provides thermo-stability. • E336 Zn2+ coordination maintains substrate affinity. Metal binding sites are present in one-third of proteins and are crucial for biological functions and structural maintenance. GH26 endo-mannanase (ManB-1601) from Bacillus sp. harbors a Zn2+ binding site which connects N (H1, H23) and C (E336)-terminal residues. Present study reveals how native circularization of ManB-1601 through Zn2+ coordination regulates the structure-function. We generated individual Zn2+ coordinating mutants and characterized them using biochemical and biophysical approaches. Contribution of individual Zn2+ coordination towards maintaining ManB-1601 stability and rigidity was in the following order H23>H1 > E336. Elimination of E336 and H23-Zn2+ coordination affected substrate hydrolysis to a greater degree than H1-Zn2+ coordination. Metal quantification of mutant proteins indicated that H23A did not contain Zn2+. Molecular dynamic simulation studies revealed disruption of H23-Zn2+ coordination leads to increased flexibility of N and C-terminal, active site loops and consequent drifting of substrate away from the active site region. Finally, mechanistic understanding on the functioning of Zn2+ site in ManB-1601 is developed wherein 1) H23 by anchoring Zn2+ ion majorly regulates the structure-function properties, 2) H1 provides thermo-stability, 3) E336 contributes towards maintaining substrate hydrolysis. [ABSTRACT FROM AUTHOR]