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Pantothenate Synthetase

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1. What is the evidence that Pantothenate Synthetase is a good target for tuberculosis? [5%]

An essential precursor for the coenzyme A and acyl carrier proteins is Pantothenate or vitamin B5 and many bacteria, fungi and plants have the denovo biosynthetic pathway to pantothenate. This pathway has four enzymes namely panB, panE, panD and panC, and as identified by bioinformatics analysis, the pathway is a possible target for the antimicrobial agents. Each of these enzymes are absent in mammals that indicates that there is a reduction in side effects due to selective inhibitors.  Genetic studies that are significant have reported that, the  M. tuberculosis associated pantothenate auxotroph that is non functioning in panD and panC, failed to initiate virulence in a mouse model of infection. A strain of M.tuberculosis that has no panD and panC, and the primary attenuating mutations of the strain of bacille Calmette–Guérin (BCG) is regarded as the candidate of  human vaccine for protection against tuberculosis.

2. Which techniques were used to detect binding in the initial fragment screening? Which program was used for docking?

Remarkable developments in biophysical, analytical and structural techniques in an effort to monitor affinities that are weak to moderate associated with interactions of protein ligands have made possible the favourable outcome as well as development of drug discovery based on fragment. Comparison of fragment screening with high throughput screening or HTS, small libraries of compounds of relatively smaller size are screened at higher concentration for the direct non covalent bonding to the target proteins. The bona fide binding hits with less complexity and affinities that are weak, constitute a point of attraction of high quality for medicinal chemistry.

The approach of molecular docking is utilised to prototype the interaction between a small molecule and a protein at the atomic level, this facilitates to behavioural characterisation of smaller molecules in the binding site of target proteins and to describe the fundamental biochemical processes. The docking process consists of two steps, prediction of ligand confirmation and its position as well as orientation within these sites, and finally assessment affinity of binding.

3. Draw the 2D structures of the two final compounds and the structures of the initial fragments (without any modification) that were used to determine these final compounds. Make sure I can tell which fragments lead to which final compound. Do not draw the structures by hand: use software identified in DAI 1

  1. Fragmentation sequence for four molecules that have a common root and grouped according to the common fragment
  2. Representation that subsumes analogus and adjacent fragments into individual nodes.

4. Calculate the log P of the 2 final compounds (4 and 8) using a programme on the web, determine the Ligand-Lipophilicity Efficiency(LLE) index and comment on the result. Show your working.

Log P calculations are based on the pool of fragments that are established in advance in the log P calculator. A unique name and value is assigned to each fragment, the log P value is the sum of values of the fragment that are present in the molecule.

  1. Ibuprofen has the typical log D vs pH profile that is the characteristic of acidic compounds, the compound has the dominant lipophilic behavior when its carboxylic group is unionized. At a higher pH values the carboxyl group becomes ionized and there is an increase in hydrophilicyt

The compound is zwitterionic and it has A1A2B1B2 molecular form and the lipophilicity of the compound will be maximum near the isoelectric point.

Ligand-Lipophilicity Efficiency

Molecular properties are quantified by the ligand efficiency measures, the size and lipophilicity in particular, of small molecules that need binding efficiency targeted drug. Ligand efficiency is the free binding energy for heavy atom count that is (LE = ∆G/HA) and lipophilic ligand efficiency LLE = pIC50 or Ki –


 optimizing the ligand efficiencies that are based on both lipophilicity and molecular size when they are set in the specific context of target, they have the potential to enhance molecular inflation.

5. Identify a compound that has been developed from an initial fragment with a non-ideal ligand efficiency (LE) value and one with an ideal LE.

The initial fragment that is with Ideal IE value is identified as the most promising fragment, and it is identified on the basis of the efficiency of ligand, confidence of the binding mode, chemical expansion vector, and synthetic tractability.

The screening hit rate and the access level to the structural biology will influence the selection process of the fragment.

The structural biology assesses the quality of the structure and ideal resolution should be high and computational chemistry reviews the specific interactions of each ligand and medicinal chemistry suggests the options from the optimization of each fragment. The combined strategy would help for fragment optimization.

The non-ideal fragment optimization selects the best fragment hits that can be suitable for work.

6.  a) Using structures downloaded from rcsb.org, tabulate the interactions (i.e. residue name and number and whether it is a hydrogen bond or hydrophobic interaction) made by the fragments that were used to design compound 8. Also tabulate whether the corresponding interactions are present in the binding for compound 8. [5%]

The insilico method has allowed to disclose that a multitargeted small molecule binds to its respective targets with low affinity, and alteration of its binding affinity can be done by the integration of confirmationally favoured groups that are functional at its ligand target interface active site. The hydrogen bonding, as well as the optimised hydrophobic interactions where ligands are stabilised at the site of the target, and assist in binding affinity and drug efficacy.

Hydrophobic Interactions and Hydrogen Bonding that are optimised at the Target-Ligand Interface

b) Discuss whether the fragments that were used to develop compound 8 bind in the same way as the corresponding parts of compound 8. [5%]

Screening initially is performed with low molecular compounds referred to as fragments is Fragment based drug discovery or FBDD. It depends on a point that there is a conservation of  fragment binding on further extension to larger ligand, has the possibility to test computationally. This condition is utilized to know whether the compound is suitable for FBDD and the prediction of fragments required for screening as well as determination if the fragment hit can be extended to higher affinity ligand.

c) Identify the linker group and discuss the contribution of interactions to the linker

The linker paradigm holds that an architectural compound has an important role in maintaining the structure. The multifunctionality of the compound originates due to interactions various groups. It will be interesting to determine that the extent to which the compound can make tertiary complexes linker compound are highly mobile and thus there free pool of molecules available for interaction with other compounds

7. Which strategy, fragment growing or fragment linking, was shown to be the best strategy and why? [20%]

For biological targets, fragment based drug design provides active compounds and fragment linking has been reported rarely.  Dynamic combinational chemistry is a powerful hit identification strategy for biological targets, there exist a synergistic combination of fragment linking and dynamic combinational chemistry.

Two unmistakable techniques revealed intense title protein inhibitors. X-beam crystallography and isothermal titration calorimetry guided the methodical elaboration of pieces distinguished from biophysical screens. As shown in the enzyme active site on the right, the excellent inhibitor was formed by connection of the lead fragments (left) with an acryl sulfonamide linker and resembles the best inhibitor discovered by the fragment-growing strategy.

8. (i) Using structures with pdb codes 3IVX and/or 3IMG, assess the suitability of autodockvina for docking compounds 1, 5 and 8 to the protein target. [15%]

Screening of ligand molecules for target protein with the help of computed aided docking is a crucial step in drug discovery. a computational filter that reduces the size of chemical library is virtual screening, in which there is an experimental screening that drastically reduces time and effort for the identification of lead.

(ii) Using autodockvina, assess whether it is possible to dock compound 5 when compound 1 is present and Assess whether it is possible to dock compound 1 when compound 5 is present. For this part you may additionally use the structures with PDB codes 3IMC and 3IME and you may need to edit the pdbfiles using notepad, e.g. to remove the ligands, associated small molecules e.g. sulfate and water molecules.

Docking of small molecules into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure based drug designing. For a thorough understanding of the structural principles that determines the strength of both ligand an accurate and fast protocol such as interface between molecular graphic system PyMOL and the molecular docking suites Autodock and Vina and determines how the docking and visualisation can help in drug designing.

(iii) Submit all relevant coordinates via FASER

(iv) Quality of structures built by TEXTAL




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Essay, Bookmy. (August 2018). Pantothenate Synthetase. Retrieved from https://www.samples.bookmyessay.com/pantothenate-synthetase/

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Essays, BookMy. (November 2018). Pantothenate Synthetase. Retrieved from https://www.samples.bookmyessay.com/pantothenate-synthetase/

Bookmyessay. November 2018. Pantothenate Synthetase. [online]. Available from: https://www.samples.bookmyessay.com/pantothenate-synthetase/ [ Accessed Friday 10th July 2020].

Essays, BookMy. (November 2018). Pantothenate Synthetase. Retrieved from https://www.samples.bookmyessay.com/pantothenate-synthetase/

Essays, Bookmy. (November 2018). Pantothenate Synthetase. Retrieved from https://www.samples.bookmyessay.com/pantothenate-synthetase/

All Answers ltd, 'Pantothenate Synthetase' (Bookmyessays.com, September 2019) https://www.samples.bookmyessay.com/pantothenate-synthetase/ accessed Friday 10th July 2020

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