INTRODUCTION:

The ponder of promoted Drugs, their biologic properties, and their quantitative Structure movement Sedate plan is the innovative handle of finding unused solutions based on the information of a organic target. Within the most fundamental sense, sedate plan includes the plan of atoms that are complementary in shape and charge to the atomic target with which they associated and tie.¹

Computerized conformational examination Grants the therapeutic chemist to foresee the drug’s three-Dimensional (3D) shape that’s seen by the receptor. With The separation and auxiliary assurance of particular receptors and the accessibility of computer program that can gauge the 3D shape of the receptor, it is conceivable to plan Atoms that will appear an ideal fit to the receptor.²

This department of chemistry is included with the Distinguish cation, plan, amalgamation, and improvement of modern Drugs that are secure and reasonable for restorative utilize in People and pets. It too incorporates relationship (QSAR).³

Advantages:

1. Sedate plan is to foresee whether a given particle will tie to a target and in the event that so how emphatically.

2. Atomic mechanics or atomic flow is most regularly utilized to appraise the quality of the Intermolecular interaction between the little particle and its organic target.

3. These strategies are moreover utilized to anticipate the adaptation of the little atom and to demonstrate conformational changes within the target that will happen when the little atom ties to it.⁴

Type of drug design:

1. Ligand based drug design (Indirect drug design)

2. Structure based drug design (Direct drug design)

3. Rational drug design

4. Computer assisted drug design⁵

MATERIAL AND METHOD:

Drug: Amantadine:

Amantadine, originally marketed as an antiviral drug for influenza A, is Adamantan-1amine. 1-Adamantylamine is a synthetic tricyclic amine and part of the adamantane group. Pharmacology of amantadine, initially marketed as an antiviral for influenza A, as an alternative to antipsychotic-induced Parkinson’s disease and avoids central nervous system and peripheral side effects of anticholinergic drugs. Its mechanism of action is unclear, but appears to involve blockade of presynaptic dopamine (DA) reuptake, facilitation of DA release, postsynaptic DA agonism, and receptor modulation. Amantadine was originally used in influenza A virus (H2N2 strain) and its antiviral activity is considered to be related to its binding to the M2 proton-selective ion channel of influenza A virus. Orally administered amantadine is well absorbed from the gastrointestinal tract and is usually administered at a dose of 100 mg twice daily for at least 14 days in adults. Amantadine has a mild diuretic effect and is mainly excreted unchanged in the urine. The lowest reported acute lethal dose is 2 g in adults.⁶

Chemical structure drawing of amantadine by using Chem Skech:

Modes of the Application:

Chem Sketch has two modes, each with different toolbar Functions: You will start in Structure mode where you can draw molecules, reactions, and schema. Switch To Draw mode to create and edit graphical objects such as reaction diagrams, orbitals, lab Equipment, and much more (read more under the Templates section below).

Draw Molecules:

Start drawing a molecule with C-C bonds by simply clicking and dragging your cursor in the Drawing Window (Structure mode). Draw Normal mode and Carbon are selected by default upon Start-up. Use Draw continuous mode to quickly link carbon atoms in or Draw Chains mode to Draw a multi-carbon chain. To draw a branched structure, click on an existing carbon atom. To Change a bond, click repeatedly on the bond to toggle between single, double, and triple, or use the other bond options to access to change the type of bond.

Fig 1: Structure of amantadine drawn

To change an atom in your molecule, select the desired atom from the left toolbar and then click a Carbon in the structure to replace it. Click Atom Properties to change the valence, charge, and Isotope of an atom.

Fig 2: All atom properties of amantadine given by software

Customize Structure: To remove an atom, click Erase and then click on an atom. To standardize bond lengths and angles, Click Clean Structure. To edit the properties and drawing style of a bond, double-click on it. You can also check for Tautomeric Forms and rotate the structure in 2D or 3D to see different views.⁷

Fig 3: Converted drawn structure into 3D view

Chemical database search:

Chemical databases are an essential part of the modern drug development process at every stage. The database allows quick access to information about the compound of interest as well as the grouping of certain chemical compounds according to structural and physicochemical properties. Chemical compounds according to structural and physicochemical properties. PubChem is the world’s largest freely accessible collection of chemical information. Search for chemicals by name, molecular formula, structure, and other identifiers Find physical and chemical properties, biological activity, safety and toxicity information, patents, bibliographic citations and more.

Search for: Amantadine

Fig 4: Amantadine

Compound CID: 2130, MF: C10H17N, MW: 151.25g/mol

UPAC Name: adamantan-1-amine, Create Date: - 2004-09⁸

PDB: Protein data bank:

The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids.

Search by using PDB ID as query: 2KQT⁹

Fig 5: Ligand (2KQT) on PDB

Autodock presentation: Docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex.¹⁰

Presentation of ligand on autodock tool:

1 Prepare target protein for docking: Autodock expects that the input protein has polar hydrogens and that all the water molecules have been removed. You will get errors if this is not the case

1.1 Open hsg1.pdb in pyMol and remove all water molecules.

1.2 Open file hsgl.pdb in ADT. File-> Read Molecule (You can rotate the structure with the middle mouse button. Zoom with the middle mouse button while holding down the shift key)

1.3 Add polar hydrogens to target structure Edit->Hydrogens->Add Make sure that you select Polar only

1.4 Save the structure: File>Save->Write PDB

Fig 6: Ligand in autodock tool with it’s no. of chain

2 Initialize ligand for docking: Before initializing a ligand, you should make sure that it has all its hydrogens attached. For this tutorial the ligand ind.pdb already has its hydrogens attached.

2.1 Hide the protein in view. Display->Show/Hide Molecule

2.2 Load the ligand file. The default file type in the file open dialog is. pdbq. Change it to pdb. Ligand->Input->Open…(AD3) Note that we used the “Open (AD3)” option and not the “Open” at the top. This is because we are going to run AutoDock3 and Not Autodock4, in which case we would have used the “Open…” Option. ADT initializes the ligand file and adds gasteiger charges. If the ligand was a peptide, it would have added Kollman charges.

2.3 Detect the root of the ligand. Ligand->Torsion Tree->Detect Root.

2.4 View rotatable bond Ligand->Torsion Tree->Choose Torsions… This opens a dialog that allows you to set which bond AutoDock is allowed to rotate. Note that amide bonds are set to non-rotatable. Click Done without changing anything.

2.5 Set rotatable bond (Active torsions) to 6 while allowing the fewest atoms to move. Ligand->Torsion Tree->Set Number of Torsions.

2.6 Save the Ligand. Ligand->Output->Save as PDBQ (AD3) In the file save dialog, explicitly type the file name “Ligand.pdbq”.

Fig 7: Ligand save as pdbqt

3 Prepare Grid map Grid is placed on the target active site and should contain all atoms that could possibly interact with the ligand. It should be large enough to allow the ligand to fully rotate.

3.1 Set target protein in which the ligand will dock. Grid->Macromolecule->Choose…(AD3) Select the protein target prepared in step 1. Immediately after the file opens ADT opens the file save dialog to save the initialized target protein. Save this structure is the directory in which you will run AutoDock. Explicitly type “Protein.pdbq”.

3.2 Set the Map types that will be used for the Grid. Grid->Set Map Types->Choose Ligand…(AD3)

3.3 Set the Grid Box position and size. Grid Box… For this exercise: Set each of the dimensions of the grid box to 60 points. Use the (2.5, 6.5, -7.5) x, y, z coordinates for the center of the box.

3.4 Save the current grid positioning File->Close Saving Current.

3.5 Save Grid file. Grid->Output->Save GPF…(AD3) In the file save dialog explicitly type “Grid.gpf”.

Fig 8: Grid box over micro molecule

4 Setup docking parameter file

4.1 Set the protein target to be docked, Docking->Macromolecule->Set filename…(AD3) Select the Protein.pdbqs file.

4.2 Select the ligand to be docked, Docking->Ligand->Choose… (AD3) A ligand parameters window opens. Leave all parameters at the default values.

4.3 Set search parameters, Docking->Search Parameters Genetic Algorithm…. Make the following changes to the parameters: Number of runs -> 50 Population size -> 50 Maximum number of energy evaluations -> 1500000. Leave the rest of the parameters at the default values

4.4 Set Docking parameters Docking Parameters… Make the following changes to the parameters: Translation -> 0.2 Quaternion -> 5.0. First way is looking for the score function your program uses. For some score functions, lower value indicates better interactions and for others, higher values indicate better interactions. Also, Look for the decomposition of the score. Normally, the score is composed by different type of Interaction/penalties like Coulomb electrostatic interaction, van der Waals interaction, H-bond Interaction, etc. This partition scheme will help you to understand which is the main mechanism 0f interaction between your ligand and the protein. This should be the main way to get conclusions about how the interaction occurs. Torsion -> 5.0 RMS Cluster tolerance SIS Leave the rest of the parameters at the default values

4.6 Set the Docking output parameter file Docking->Output->Lamarckian GA… (AD3) In the file save dialog explicitly type “Dock.dpf”.

5 Running Auto Grid and Autodock, AutoDock and AutoGrid have to be run in the same directory as Ligand.pdbq, Protein.pdbq Dock.dpf.

5.1 Run AutoGrid 3 in the command line Autogrid 3 -p Grid.gpf-1 Grid.glg

5.2 Run AutoDock3 in the command line Autodock3 -p Dock.dpf-1 Dock.dlg

6 View Docking Results

6.1 When AutoDock completed its run, you can view the results in ADT. Analyze->Dockings->Open… Open the Dock.dlg file

6.2 Load macromolecule into view Analyze->Macromolecule-. Choose

6.3 Select the macromolecule Select->Direct Select->Molecule List … Make sure that only the macromolecule is selected.

6.4 Color the atoms of the macromolecule Color->by Atom Type

6.5 Compute the molecular surface of the macromolecule Compute->Molecular Surface->Compute Molecular Surface

6.6 View the conformations Analyze->Conformations->Play … Use the player to look at the conformations

6.7 View conformational clusters Analyze->Clustering->Show … Select a cluster to view

6.8 Set play options Press & on the player dialog select Show Info and Build Hydrogen Bonds.¹¹

RESULT:

This study aims to know the effectiveness of using ChemSketch in teaching molecular forms of hydrocarbons to used is expected to solve this problem by using ChemSketch Molecular Docking to position the computer-generated 3D structure of small ligands in the receptor structure in multiple orientations, the different fits and locations. This method is useful in drug discovery and medicinal chemistry because it provides information on molecular. Docking has become an integral part of computer-aided design and drug discovery (CADDD). Amantadine was initially used in influenza A virus (H2N2 strain) and its activity Its antiviral activity is considered to involve binding to the M2 proton of the influenza A virus, a selective ion channel. Orally administered amantadine is well absorbed from the gastrointestinal tract and is usually administered at a dose of 100 mg twice daily for at least 14 days in adults. Amantadine has a mild diuretic effect and is mainly excreted unchanged in the urine. The lowest reported acute lethal dose is 2 g in adults.

DISCUSSION:

In molecular docking studies, the integration of tools like ChemSketch, PubChem, PDB, and AutoDock provides a comprehensive workflow from the preparation of chemical structures to the prediction of their interactions with biological targets. ChemSketch assists in drawing and optimizing ligand structures, PubChem offers a vast database of chemical compounds and their properties, PDB provides high-quality 3D structures of biological macromolecules, and AutoDock performs the docking simulations to predict binding modes and affinities. This combination of tools enhances the efficiency and accuracy of molecular docking studies, aiding in the discovery and development of new therapeutic agents. AutoDock is used to perform the actual docking simulations. Researchers input the prepared structures of ligands and receptors, run the docking algorithms, and analyze the results to predict the most favorable binding poses and affinities.

REFERENCES:

1. Zhou, Shu-Feng, and Wei-Zhu Zhong. Drug design and discovery: principles and Applications. Molecules. 2017; 22(2): 279.

2. Alagarsamy, V. Textbook of Medicinal Chemistry. Vol I-E-Book. Vol. 1. Elsevier Health Sciences, 2013.

3. Foye, William O. Foye’s Principles of Medicinal Chemistry. Lippincott Williams and Wilkins, 2008.Victoria F. Roche. S. William Zito, Seventh Edition, Chapter 2-Page no. 29.

4. Tzotzos, Susan J. Peptide Drugs of the Decade. The European Peptide Society. 2020.

5. Sigg, Jérôme. Production of drug-delivery systems with Ibuprofen through encapsulation in nanofibers and-particles with core-shell architecture. 2017.

6. Yee, J. xPharm: The comprehensive pharmacology reference. xPharm: The Comprehensive Pharmacology reference. Editor Bylund SJEADB, editor. (Elsevier (2008).

7. Mahaffey, Angela L. A complementary laboratory exercise: Introducing molecular structure–Function topics to undergraduate nursing health professions students. Journal of Chemical Education. 2019; 96(10): 2188-2193

8. https://pubchem.ncbi.nlm.nih.gov/#query=Amantadine

9. https://www.rcsb.org/

10. Jakhar, Ritu, et al. Relevance of molecular docking studies in drug designing. Current Bioinformatics. 2020; 15(4): 270-278.

11. Huey, Ruth, Garrett M. Morris, and Stefano Forli. Using AutoDock 4 and AutoDock vina with AutoDock Tools: a tutorial. The Scripps Research Institute Molecular Graphics Laboratory 10550.92037 (2012): 1000.

Received on 06.04.2024 Modified on 29.05.2024

Asian J. Pharm. Res. 2024; 14(3):326-330.

DOI: 10.52711/2231-5691.2024.00051