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Molecular Docking: A Computational Catalyst For Drug Development.

Introduction Types of docking Steps of molecular docking Applications References.

INTRODUCTION.

Molecular Docking. Binding Affinity. Preferred Orientation.

Why Molecular Docking ?. Understanding the Biomolecular interaction.

Types of Molecular Docking. Rigid Docking Flexible - Rigid Docking Flexible Docking.

Rigid Docking In rigid docking, the internal geometry of both the receptor and ligand are treated as rigid..

Flexible Rigid Docking In Flexible - rigid docking , ligand is flexible and receptor is rigid..

Flexible Docking An enumeration on the rotations of one of the molecules (usually smaller one) is performed. Every rotation the energy is calculated ; later the most optimum pose is selected..

Steps of Molecular Docking.

Protein Preparation. Go to RCSB PDB(Protein Data Bank) Choose Protein [E.g. Antitumor Protein , Antibacterial Protein] Download it in PDB Format File and save the file Open AutoDock Vina.

[image] RCSB PDB Depsn • Search • Vtsuauze Anayze Download Learn • Atnut careers COVIL)-19 Display Fles FASTA sequence @Download FIB Bido$cal AssemUy 1 0 Explore in Structure Sequence Annotations I Validatnn Repott I Ligand Interaction (832) Global Symmetry Asymmetric. Cl O Global Echiometry• Mmomer - A10 THE CRYSTAL STRUCTURE OF E.COLI PEPTI ACTINONIN DOI: Classification: HYDROLASE organism(s): Escherichia coli Expressm System• . a-scnencnz SL21(DE3) Mutation(s): No O 2001-10-17 Deposition Autlor(s): Clements, J.M., Beckett P, Brown. R, ld., daker, P.J., Rodgers, H,f, Barynin, V, Rte. O.W., Hunter, POBx/mmClF Format POBxlmmClF Format (gz) BinaryCIF Format (gz) POB Format POB Format (gz) PDBMUXML Format Validation (WL gz) Validation (CIF .gz) Biological Assembly 1 (CIF - gz)O Biological Assembly 2 (CIF - gz) Biological Assembly 3 (CIF D WITH , Whittake Full Re Experimental Data Snapshot Meth0d: DIFFRACTION Resolution: 1.75 Å R.wue Free: 0150 R-value worx: O. 190 R-value Observed: O, 191 WWPDB BiologicalAssembly I @7gg) IL, Biclootal Assemblv 2 (P03 azi.

[image] File 3DGraphics Edit Select Display Color Hydrogen Bonds Compute Grid3D Help -gand Flexible Residues Dashboard Scenario Grid Docking Run Analyze Tools All Molecules Current Selection receptor s L 3 C RMSLCI oooocovv ooocovv oeoooovv.

Go to Read Molecule – Select Downloaded Protein (PDB Format File) Go to Edit and remove water molecules, Add Polar Hydrogen Molecules, Add Kollman Charges . Now save the Protein File as Protein PDBQT FILE (Protein Data Bank, Partial Charge(Q) ,Atom type (T)Format).

[image].

Draw Ligand on Chem Draw Open the ligand Chem draw file on Chem Draw 3D Minimize the energy of ligand Save the Ligand File.

Setting Up Docking Simulation. Grid generation : This box will be defined by its center coordinates and size (x, y, and z dimensions)..

[image] File 3D Graphics Edit Select Display Color Hydrogen Bonds Compute JDT4 2 Ligand Flexible Residues Grid Docking Run Analyze Dashboard Scenario Tools Sei 7' Grid Options Grid3D Help All Molecules Current Selection E Vpdf receptor Center View Help current Total map: 64000 number of points in x.dimension: number of points in y-dimension: number of points in z.dimension: Spacing (angstrom): Center Grid Box: y center: z center: .279 17.88.

Configuration File :This file specifies Paths to the prepared protein and ligand files. The center coordinates and size of the search space grid. Optional parameters like exhaustiveness (number of docking poses to be generated)..

Running the Docking Simulation. Open a command prompt or terminal window. Navigate to the directory containing Vina and your configuration file. Execute the Vina command. Vina will run the docking simulation and generate output files containing information about the docked poses, binding energies, and other relevant data..

mode | affinity | dist from best mode | (kcal/mol) | rmsd l.b.| rmsd u.b. --++-+ 1 -6.9 0.000 0.000 2 -6.5 2.653 3.498 3 -6.4 2.939 5.167 4 -6.2 2.366 4.712 5 -5.7 2.968 5.469 6 -5.6 8.216 10.781 7 -5.6 18.099 19.746 8 -5.5 20.341 21.594 9 -5.2 21.023 22.216.

[image] No License File For Eualuation Only (O days remaining).

Applications of Molecular Docking. Drug Discovery: Screens vast libraries of molecules to identify potential drugs that bind well to target proteins. Bioremediation: Predicts how pollutants fit into enzymes, aiding design of pollution-degrading microbes. Pesticide Design: Simulates how chemicals bind to pests or weeds, allowing targeted control. Material Science: Designs new materials with specific properties by virtually testing how molecules bind..

Limitations of Molecular Docking. Lack of confidence in scoring functions to give accurate binding energies. Unsolved problem of a water molecule in the binding pocket during docking. Rigid receptor considerations.

References. Agu, P. C., Afiukwa, C. A., Orji, O. U., Ezeh, E. M., Ofoke, I. H., Ogbu, C. O., Ugwuja, E. I., & Aja, P. M. (2023). Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Scientific reports, 13(1), 13398. https://doi.org/10.1038/s41598-023-40160-2 Stanzione, F., Giangreco, I., & Cole, J. C. (2021). Use of molecular docking computational tools in drug discovery. Progress in medicinal chemistry, 60, 273–343. https://doi.org/10.1016/bs.pmch.2021.01.004.

Eberhardt, J., Santos-Martins, D., Tillack, A. F., & Forli, S. (2021). AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. Journal of chemical information and modeling, 61(8), 3891–3898. https://doi.org/10.1021/acs.jcim.1c00203 Sahu, D., Rathor, L. S., Dwivedi, S. D., Shah, K., Chauhan, N. S., Singh, M. R., & Singh, D. (2024). A Review on Molecular Docking As an Interpretative Tool for Molecular Targets in Disease Management. Assay and drug development technologies, 22(1), 40–50. https://doi.org/10.1089/adt.2023.060.

Thank You.