Proposing of fungal endophyte secondary metabolites as a potential inhibitors of 2019-novel coronavirus main protease using docking and molecular dynamics.

In this study, the inhibitory potential of 99 fungal derived secondary metabolites was predicted against SARS-CoV-2 main protease by using of computational approaches. This protein plays an important role in replication and is one of the important targets to inhibit viral reproduction. Among the 99 reported compounds, the 9 of them with the highest binding energy to Mpro obtained from the molecular docking method were selected for the molecular dynamic simulations. The compounds were then investigated by using the SwissADME serve to evaluate the compounds in terms of pharmacokinetic and druglikness properties. The overall results of different analysis show that the compound RKS-1778 is potentially more effective than others and form strong complexes with viral protease. It also had better pharmacokinetic properties than other metabolites, so predicted to be a suitable candidate as anti SARS-CoV-2 bioactive.Communicated by Ramaswamy H. Sarma.

Determining the stoichiometry and binding constant of Lamotrigine with human serum albumin using voltammetry analysis and molecular modeling.

In this study, the interaction of an anticonvulsant drug that used in the treatment of epilepsy, Lamotrigine (LTG) with the most important transport protein of the blood, human serum albumin (HSA) has been studied by using the electrochemical methods and molecular modeling techniques. For this purpose, a simple carbon paste electrode (CPE) was applied for electrocatalytic oxidation and investigation of LTG interaction with HSA. The stoichiometry of the complex between LTG and HSA and the binding constant (Kb) of the reaction were calculated from the calibration curves. The results show that binding of LTG to HSA formed two complexes with different stoichiometries with Kb1 (2.46 × 103) and Kb2 (1.75 × 107), respectively. In agreement with the experimental data, molecular modeling approach also confirmed that LTG can bind to the subdomain IIA and IB of HSA.Communicated by Ramaswamy H. Sarma.

Simultaneous Determination of Multicomponent Dosage Forms Using Benchtop NMR Spectroscopy: Application to Phenytoin-Phenobarbital Combination.

The use of nuclear magnetic resonance (NMR) spectroscopy as a tool for determining pharmaceutical molecules in bulk drugs and their dosage forms is growing. New advancements in benchtop NMR spectrometers with cryogen-free magnets have made this technique more appealing and accessible. Herein, we developed a method using a benchtop NMR spectrometer to quantify phenytoin (PhT) and phenobarbital (PhB) in bulk and combined dosage forms. The results were compared to those obtained by high performance liquid chromatography (HPLC) as a well-characterized procedure. This method is simple, low cost, relatively fast, and non-inferior to HPLC in terms of figures of merit.

Shedding light on the structural properties of lipid bilayers using molecular dynamics simulation: a review study.

In recent years, a massive increase has been observed in the number of published articles describing accurate and reliable molecular dynamics simulations of lipid bilayers. This is due to several reasons, including the development of fast and efficient methods for treating long-range electrostatic interactions, significant progress in computer hardware, progress in atomistic simulation algorithms and the development of well-validated empirical molecular mechanical force fields. Although molecular dynamics is an effective approach for investigating different aspects of lipid bilayers, to the best of our knowledge, there is no review in the literature that explains the different analyses that can be carried out with membrane simulation. This review gives an overview about the some of the most important possible analyses, technical challenges, and existing protocols that can be performed on the biological membrane by molecular dynamics simulation. The reviewed analyses include the degree of membrane disruption, average area per lipid, probability distributions for the area per lipid molecule, membrane thickness, membrane area compressibility, lateral diffusion, rotational diffusion, order parameters, head group tilt, electron density profile, mass density profile, electrostatic potential profile, ordering of vicinity waters, number of hydrogen bonds, and radial distribution function.

Correction: Shedding light on the structural properties of lipid bilayers using molecular dynamics simulation: a review study.

[This corrects the article DOI: 10.1039/C8RA08441F.].

Discovery of Novel Glucagon Receptor Antagonists Using Combined Pharmacophore Modeling and Docking.

Glucagon and the glucagon receptor are most important molecules control over blood glucose concentrations. These two molecules are very important to studies of type 2 diabetic patients. In literature, several classes of small molecule antagonists of the human glucagon receptor have been reported. Glucagon receptor antagonist could decrease hepatic glucose output and improve glucose control in diabetic patients. In this research, to identify novel and diverse leads for use in potent glucagon receptor antagonist design, a ligand-based pharmacophore modeling, was developed using the best conformations of training set compounds. The best five features pharmacophore model, called Hypo1, includes, hydrogen bond acceptors, two hydrophobic, and positive ionizable features, which has the highest correlation coefficient (0.805), cost difference (64.38), low RMS (2.148), as well as it shows a high goodness of fit and enrichment factor. The generated pharmacophore model has been validated by using a series of similar structures with varying affinities for the glucagon receptor. Then, the developed model has been applied as a search query in different database searching with the main objective of finding novel molecules which have the potential to be be modified into novel lead compounds. As a result, some hit molecules were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. The results from pharmacophore modeling and molecular docking are complementary to each other and could serve as a useful way for the discovery of potent small molecules as glucagon receptor antagonist.

Direct evidences for the groove binding of the Clomifene to double stranded DNA.

It has been reported that the antiestrogen Tamoxifen induces liver tumors in rats and genotoxic effects in vitro through DNA interaction. So, it can be proposed that its structural analogue, Clomifene, also can bind to DNA. To test this hypothesis, the DNA binding properties of Clomifene have been studied by absorption spectroscopy, fluorescence spectroscopy, cellular uptake, cell viability, cell proliferation and molecular modeling techniques. Evidences are provided that Clomifene could interact with DNA via minor groove interaction mode. The negative ΔG value implied that the interaction occurred between DNA and Clomifene spontaneously. Also, the positive ΔH and positive ΔS values indicated that the binding of Clomifene with DNA is mainly entropy driven and the enthalpy is unfavorable parameter. This also suggests that the hydrophobic interaction plays a major role in the binding with overall binding constant of K=5.645×107M-1 at 298K. From the results of docking, it can be concluded that Hydrogen bonds is also one of the most important interactions. The increase in entropy of system after binding might be due to the destruction of the DNA structure.

Experimental and computational studies on the binding of diazinon to human serum albumin.

In the present research, the binding properties of diazinon (DZN), as an organophosphorus herbicide, to human serum albumin (HSA) were investigated using combination of spectroscopic, electrochemistry, and molecular modeling techniques. Changes in the UV-Vis and FT-IR spectra were observed upon ligand binding along with a significant degree of tryptophan fluorescence quenching on complex formation. The obtained results from spectroscopic and electrochemistry experiments along with the computational studies suggest that DZN binds to residues located in subdomains IIA of HSA with binding constant about 1410.9 M-1 at 300 K. From the thermodynamic parameters calculated according to the van't Hoff equation, the enthalpy change ΔH° and entropy change ΔS° were found to be -16.695 and 0.116 KJ/mol K, respectively. The primary binding pattern is determined by hydrophobic interaction and hydrogen binding occurring in so-called site I of HSA. DZN could slightly alter the secondary structure of HSA. All of experimental results are supported by computational techniques such as docking and molecular dynamics simulation using a HSA crystal model.

Insights from a combination of theoretical and experimental methods for probing the biomolecular interactions between human serum albumin and clomiphene.

In this study, the interaction of clomiphene (CLO), a non-steroidal and ovulatory stimulant drug employed in the treatment of infertility, with human serum albumin (HSA), the most abundant plasma transport protein, was investigated using spectrofluorometric, FT-IR, UV-Vis, and molecular modeling methods. The obtained results indicated that the binding of CLO to HSA led to intense fluorescence quenching of HSA via a static quenching mechanism, and that the process of CLO binding to HSA was enthalpy driven. By using experimental and theoretical methods, it was confirmed that as a result of binding CLO, slight conformational changes in HSA occurred. Also, the negative ΔH of interaction indicated that the binding of CLO with HSA was mainly enthalpy driven. The experimental and computational results suggested that hydrogen bonds and van der Waals interactions played a major role in the binding, with overall binding constants of K = 3.67 × 109 M-1 at 286 K and 6.52 × 105 mol L-1 at 310 K. Moreover, the results of molecular modeling showed that Asp234, Phe228, Leu327, and Arg209 in HSA had the highest interaction energies with the ligand.

A coupling of homology modeling with multiple molecular dynamics simulation for identifying representative conformation of GPCR structures: a case study on human bombesin receptor subtype-3.

In this study, a computational pipeline was therefore devised to overcome homology modeling (HM) bottlenecks. The coupling of HM with molecular dynamics (MD) simulation is useful in that it tackles the sampling deficiency of dynamics simulations by providing good-quality initial guesses for the native structure. Indeed, HM also relaxes the severe requirement of force fields to explore the huge conformational space of protein structures. In this study, the interaction between the human bombesin receptor subtype-3 and MK-5046 was investigated integrating HM, molecular docking, and MD simulations. To improve conformational sampling in typical MD simulations of GPCRs, as in other biomolecules, multiple trajectories with different initial conditions can be employed rather than a single long trajectory. Multiple MD simulations of human bombesin receptor subtype-3 with different initial atomic velocities are applied to sample conformations in the vicinity of the structure generated by HM. The backbone atom conformational space distribution of replicates is analyzed employing principal components analysis. As a result, the averages of structural and dynamic properties over the twenty-one trajectories differ significantly from those obtained from individual trajectories.

Molecular insight into the Grandivitin- matrix metalloproteinase 9 interactions.

Grandivitin (GRA), a natural coumarin, can inhibit Matrix metalloproteinase 9 (MMP9). Binding characteristics are therefore of interest for pharmacodynamics of GRA and coumarin derivatives. A combination of spectroscopic methods and molecular modeling techniques was used to characterize interaction of GRA with MMP9. Fluorescence spectroscopy showed that GRA could quench the MMP9 fluorescence spectra. Changes in the UV-Vis and FT-IR spectra were observed upon ligand binding along with a significant degree of tryptophan fluorescence quenching on complex formation. Fluorescence studies showed that GRA has an ability to quench the intrinsic fluorescence of MMP9. Molecular modeling analysis showed that GRA to be bound in the large hydrophobic cavity of MMP9. Further investigation of the binding site of GRA within the MMP9 molecule suggested that hydrophobic contacts, hydrogen bond formation and electrostatic interactions account for the binding of GRA. According molecular dynamics (MD) simulation results the ligand can interact with the protein, with affecting the secondary structure of MMP9 and with a modification of its tertiary structure. The biological significance of this work is evident because MMP9 serves as a potential target protein for anticancer agents. The binding study of GRA with MMP9 is of great importance in pharmacy, pharmacology and biochemistry. This work can provide some key data to clinical research and supply the theoretical basis for the new drug candidate designing.

Multi-spectroscopic and molecular modeling investigation of the interactions between prantschimgin and matrix metalloproteinase 9 (MMP9).

The binding of prantschimgin (PRAN) to matrix metalloproteinase 9 (MMP9) was investigated using multiple techniques. Fluorescence spectroscopy showed that PRAN could quench the MMP9 fluorescence spectra. Changes in the UV/vis and Fourier transform infrared (FTIR) spectra were observed upon ligand binding, along with a significant degree of tryptophan fluorescence quenching on complex formation. The interaction of PRAN with MMP9 has also been studied using molecular docking and molecular dynamics (MD) simulation. The binding models demonstrated aspects of PRAN's conformation, active site interaction, important amino acids and hydrogen bonding. Computational mapping of the possible binding site of PRAN revealed that the ligand is bound in a large hydrophobic cavity of MMP9. The MD simulation results suggested that this ligand can interact with the protein, with little affecting the secondary structure. The results not only lead to a better understanding of interactions between PRAN and MMP9, but also provide useful data about the influence of PRAN on the structural conformation. The data provided in this study will be useful for designing a new agonist of MMP9 with the desired activity.

Exploring binding properties of sertraline with human serum albumin: Combination of spectroscopic and molecular modeling studies.

Human serum albumin (HSA)-drug binding is an important factor to determine half life and bioavailability of drugs. In the present research, the interaction of sertraline (SER) to HSA was investigated using combination of spectroscopic and molecular modeling techniques. Changes in the UV-Vis, CD and FT-IR spectra as well as a significant degree of tryptophan fluorescence quenching were observed upon SER-HSA interaction. Data obtained by spectroscopic methods along with the computational studies suggest that SER binds to residues located in subdomain IIA of HSA. Analysis of spectroscopic data represented the formation of 1:1 complex, significant binding affinity, negative values of entropy and enthalpy changes and the essential role of hydrophobic interactions in binding of SER to HSA. The binding models were demonstrated in the aspects of SER's conformation, active site interactions, important amino acids and hydrogen bonding. Computational mapping of the possible binding site of SER confirmed that the ligand to be bound in a large hydrophobic cavity of HSA. In accordance with experimental data, computational analyses indicated that SER binding does not alter the secondary structure of the protein. The results not only lead to a better understanding of interaction between SER and HSA but also provide useful data about the influence of SER on the protein conformation.

Combined spectroscopy and molecular modeling studies on the binding of galbanic acid and MMP9.

The molecular mechanism of galbanic acid (GBA) binding to matrix metalloproteinase 9 (MMP9) was investigated by fluorescence quenching, absorption spectroscopy, FT-IR, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of MMP9 was quenched by GBA. The titration of MMP9 by various amount of GBA was also followed by UV-Vis absorption spectroscopy. The results revealed that GBA, as a biologically active sesquiterpene coumarin derivative, has an ability to bind strongly to MMP9. Molecular docking results indicated that the main active binding site for GBA has been located in a hydrophobic cavity in the vicinity of Zn atom. Moreover, MD simulation results suggested that GBA as a coumarin derivative can interact with MMP9, without affecting the secondary structure of MMP9. MD simulations, molecular docking as computational methods from one hand and experimental data from other hand reciprocally supported each other.

Constructing an atomic-resolution model of human P2X7 receptor followed by pharmacophore modeling to identify potential inhibitors.

The P2X purinoceptor 7 (P2X7R) is a trimeric ATP-activated ion channel gated by extracellular ATP. P2X7R has important role in numerous diseases including pain, neurodegeneration, and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. In this prospective, the discovery of small-molecule inhibitors for P2X7R as a novel therapeutic target has received considerable attention in recent years. At first, 3D structure of P2X7R was built by using homology modeling (HM) and a 50ns molecular dynamics simulation (MDS). Ligand-based quantitative pharmacophore modeling methodology of P2X7R antagonists were developed based on training set of 49 compounds. The best four-feature pharmacophore model, includes two hydrophobic aromatic, one hydrophobic and one aromatic ring features, has the highest correlation coefficient (0.874), cost difference (368.677), low RMSD (2.876), as well as it shows a high goodness of fit and enrichment factor. Consequently, some hit compounds were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. Among these compounds, six potential molecule were identified as potential virtual leads which, as such or upon further optimization, can be used to design novel P2X7R inhibitors.