ARGUSLAB MANUAL PDF DOWNLOAD

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It's getting a little dated by now, but remains surprisingly popular. To date, there are > 20, downloads. ArgusLab is freely licensed. You don't need to sign. for personal use from hypmarevlimist.gq By the end of this tutorial, you will know. • how to build molecules in ArgusLab an atom at a time;. Tutorial argus lab - Download as PDF File .pdf), Text File .txt) or view presentation slides online. arguslab docking.


Arguslab Manual Pdf Download

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Docking With ArgusLab - Download as Powerpoint Presentation .ppt), PDF File ( .pdf), Text 4owe+er, manual mo#ifications to a!o+e ma$!e #one if #esire#. programs before performing large-scale virtual screening experiments. Before this exercise (PDB: code 2JFF) can be freely accessed and downloaded from the Brookhaven in ArgusLab program (Arguslab icon is located on your desktop). Download ArgusLab Design complex molecular Free download · ArgusLab free download Other programs to consider. ChemSketch

The structure was cleaned in 3D format and energy was minimized using Marvin sketch software. Docking Methodology After the preparation of the protein and ligand, molecular docking studies were performed by ArgusLab 4.

ArgusLab 4. The stability of each docked pose was evaluated using ArgusLab energy calculations and the number of hydrogen bonds formed [ 17 ].

Molecular Docking Study To perform docking one first needs to define atoms that make up the ligand and the binding sites of the protein where the ligand should bind.

The ligand cleaned riboflavin molecule was then introduced and docking calculation was allowed to run using shape-based search algorithm and AScore scoring function. The scoring function is responsible for evaluating the energy between the ligand and the protein target. For each rotation, torsions are created and poses conformations are generated during the docking process [ 11 ].

For each complex, 10 independent runs were conducted and one pose was returned for each run.

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The best docking model was selected according to the lowest AScore calculated by ArgusLab, and the most suitable binding conformation was selected on the basis of hydrogen bond interactions between the ligand and protein near the substrate binding site. The lowest energy poses indicate the highest binding affinity as high energy produces the unstable conformations.

Results and Discussion Minimized structure of riboflavin is given in Figure 1. Docking studies of the compound riboflavin with each of the three enzymes having PDB codes 1ccw, 1egm, and 3iv9 were carried out by ArgusLab 4.

Journal of Computational Medicine

The least binding energy exhibits the highest activity which has been observed by the ranking of poses generated by AScore scoring function of ArgusLab and is given in Table 1. Table 1: Binding energies of riboflavin coenzyme B12 containing enzyme complex by AScore scoring function of ArgusLab. Figure 1: Minimized structure of riboflavin. Atoms in red are oxygen, blue are nitrogen, grey are carbon, and white are hydrogen. The number of hydrogen atoms is indicated in light green color.

List of hydrogen bonds between riboflavin and coenzyme Bdependent enzymes is given in Table 2. The best fitted poses adopted by riboflavin docked into enzymes 1ccw, 1egm, and 3iv9 are shown in Figures 2 , 3 , and 4 , respectively.

Table 2: List of hydrogen bonds between riboflavin and coenzyme B12 containing enzymes. Figure 2: Docking of riboflavin into enzyme glutamate mutase [ 13 ].

Riboflavin and protein binding sites are shown in element colors in wireframe and thick stick models, respectively, whereas cyanocobalamin is represented in pink stick model. Inhibitor TAR is seen in green color in thick stick. Figure 3: Docking of riboflavin into enzyme diol dehydratase [ 14 ]. Riboflavin and protein binding sites are shown in element colors in wireframe and thick stick models, respectively, whereas cyanocobalamin is represented in pink color in thick stick.

Figure 4: Docking of riboflavin into enzyme methionine synthase [ 15 ]. In the present study, cyanocobalamin coenzyme was taken as an active ligand instead of cocrystallized inhibitor D-tartaric acid, to bind with the compound riboflavin in order to examine a possible mode of interaction between these two vitamins in an enzyme system.

The docked binding mode of riboflavin was manually inspected in order to verify that it effectively binds to the catalytic site. The docking results of riboflavin with each of the individual enzymes are as follows. In Figure 2 riboflavin seemed to bind at the lower axial end of the coenzyme B12 with the base 5,6-dimethylbenzimidazole DMB by replacing water molecules.

The oxygen O2 of carbonyl group of riboflavin binds with nitrogen atom NH of amino acid residue Gly The hydrogen bond distance between these groups is 2. Another hydrogen bond was formed between the nitrogen atom N1 of riboflavin and NH of amino acid Thr at a distance of 2.

No interaction was observed between the riboflavin and cocrystallized inhibitor, D-tartaric acid. In glutamate mutase, the elongation of Co—N bond probably contributes to the weakening of Co—C bond in the coenzyme [ 13 ]. Therefore, the docked position and conformation of riboflavin revealed that the compound may inhibit the usual catalytic process of the enzyme by altering the conformational change in the nucleotide base, which plays an important role in initiating the Co—C bond cleavage and thus hinders the continuous progress of radical reactions.

The relative conformation and arrangement of cofactor and substrate also play a part in this aspect. The calculated AScore shows a significant affinity of riboflavin towards the enzyme glutamate mutase.

These amino acid residues have been found to form the hydrophobic contacts with the inhibitor 1, 2-propanediol and play an important role in holding the substrate in the active site [ 14 ]. Three hydrogen bonds were formed with this enzyme; the nitrogen atom N5 of riboflavin interacted with the sulphur SH of amino acid residue Cys The hydrogen bond distance between these groups was found to be 2.

Another two hydrogen bonds were formed between the nitrogen N1 of riboflavin and oxygen atom of Ser at a distance of 2. Methionine Synthase Figure 3 shows the binding of riboflavin near the cofactor making contact with amino acid residue His The oxygen atom O4 of the carbonyl group of riboflavin was hydrogen bonded to N-atom of the His at a distance of 2. Another hydrogen bonding was seen between the N-atom of His and the carbonyl oxygen O2 of riboflavin at a distance of 2.

His has been found to act as transient intermediate in the reductive reactivation and conformational transition of cobalt following methylation in methionine synthase-dependent enzyme catalysis [ 15 ]. Therefore, we may assume that riboflavin may inhibit the important catalytic step of the enzyme, that is, reactivation and methylation probably by making contact with the same amino acid residue His that is involved in the reaction. The binding energy also shows a significant ligand-receptor complex with this enzyme.

Conclusion By analyzing the docking results we hypothesized that riboflavin might have inhibitory activity against cobalamin coenzymes. Glutamate mutase and diol dehydratase can be considered as important targets for the development of antibiotics.

Other useful therapeutic drugs can also be synthesized to enhance the function of enzyme methionine synthase as it converts homocystein into methionine and requires methylcobalamin coenzyme for its function.

Inactivation of this coenzyme leads to the elevated levels of homocystein in blood and urine and may result in clotting and in long-term damage to the arteries stroke and heart attack. Therefore, the interaction of vitamin B2 and B12 and their role in important metabolic reactions in the body should be considered before preparing multivitamin complexes. The fact that riboflavin participates in energy-based metabolic reactions may play an important role in enzyme catalysis which depends on a delicate energy balance for different reaction pathways.

The local amino acids and substrates in the active sites of the enzymes may function in this respect. Further experimental approaches can be adopted to probe the effect of structural alterations of flavin group of compounds in the catalytic properties of coenzyme Bdependent enzymes.

References K. Gruber, B. Puffer, and B. Randaccio, S.

Geremia, N. Demitri, and J.

Banerjee and S. Sigel, H. Additionally there are several residues that are predicted to be important for MPEP binding but that have not yet been experimentally verified colored green in Table 2. For the binding of the positive modulator 3,3'-DFB, it was concluded from site-directed mutagenesis that M, S and T are critical for binding and modulatory function [ 19 ]. All of these residues are predicted to be part of the 3,3'-DFB binding pocket in the inactive model, but S and T are not present in the active model.

In addition, we predict several residues to be part of the binding pockets that have not been investigated previously shown in green in Table 2.

Thus, the comparison of the predicted ligand binding pockets in mGluR5 inactive and active models with the available experimental site directed mutagenesis data strongly validates our models.

In addition, we generated testable hypotheses on important residues previously not investigated, and provide evidence that there may be differences in the roles of the amino acids in the binding pocket depending on the conformation of the receptor.

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Analysis of binding energies The above in-depth analysis of the mGluR5 binding pocket suggests that there may be significant differences between the interactions made by negative and positive modulators with mGluRs depending on the conformation state of the receptor.

To test if there is a general trend that distinguishes the action of positive and negative modulators on the receptors, we quantified the overall binding energies for the 24 different ligands with known modulatory nature positive versus negative.

Table 1 shows the binding energies of the ligand-protein complexes calculated by ArgusLab and AutoDock and Figure 4 plots the difference between the respective energies for active and inactive conformations.

Where the energies for the active and inactive conformations were very similar, the docking was repeated three times to estimate the error on the predictions indicated in Table 1 and Figure 4. In general, the results obtained with ArgusLab were less variable between repeated runs than those obtained with AutoDock.

A total of 9 ligands were experimentally shown to act as positive modulators of specific subtypes, 14 ligands were negative modulators and one ligand was neutral.

In general, the positive modulators bound with more favorable energy to the model of the active mGluR conformation based on the rhodopsin ANM model [ 18 ], while the negative modulators bound with more favorable energy to the model of the inactive mGluR conformation based on the rhodopsin inactive, dark-state [ 17 ]. The neutral ligand, 5MPEP, showed relatively little differences between the energies of the inactive and the active models, but was consistently better docked to the active model using both programs.

Docking With ArgusLab

There were also more incidences in which AutoDock was not able to predict binding for the ligands. Five of the predictions for negative modulators and one positive modulator obtained with AutoDock were near or beyond the accuracy limit of AutoDock as judged by the error obtained when multiple independent docking experiments were carried out.There were also more incidences in which AutoDock was not able to predict binding for the ligands.

The hydrogen bond distance between these groups was found to be 2.

A total of 9 ligands were experimentally shown to act as positive modulators of specific subtypes, 14 ligands were negative modulators and one ligand was neutral.

The stability of each docked pose was evaluated using ArgusLab energy calculations and the number of hydrogen bonds formed [ 17 ]. In the present study, cyanocobalamin coenzyme was taken as an active ligand instead of cocrystallized inhibitor D-tartaric acid, to bind with the compound riboflavin in order to examine a possible mode of interaction between these two vitamins in an enzyme system.

Computational Methodology 2.