MOLECULAR DOCKING AND TYPES OF MOLECULAR DOCKING.pptx

Docking is a molecular modelling method ( using a computer software ) aimed at discovering the optimal fit between a ligand ( Drug ) and its binding site.
It is a structure based technique which attempts to find the best match between two molecules. Rigid Docking- Both the ligand and receptor molecules are regarded as rigid bodies .
No conformational changes are allowed.
Flexible Docking- Atleast one of the molecules is allowed to flexible.
Extra Precision Docking- It is a module available in schrodinger unit.
The purpose is to rule out false positives and to provide a better correlation between good poses and good scores.
It is employed to refine and optimize docking results.
Provide more reliable predictions of ligand- receptor interactions
Only top scoring ligands should be docked using XP mode.
Manual Docking- It is a hands on approach to molecular docking
Here manually positions to ligand in the binding site
This involves directly placing and adjusting the ligand within the receptor active site using molecular visualization software

1. TYPES OF MOLECULAR DOCKING HONEY HETTY 2 ND SEM MPHARM 2024 DEPARTMENT OF PHARMACEUTICAL CHEMISTRY ST. JAMES’ COLLEGE OF PHARMACEUTICAL SCIENCES, CHALAKUDY 1

2. CONTENTS MOLECULAR DOCKING TYPES RIGID DOCKING FLEXIBLE DOCKING MANUAL DOCKING EXTRA PRECISION DOCKING REFERENCES 2

3. MOLECULAR DOCKING Docking is a molecular modelling method ( using a computer software ) aimed at discovering the optimal fit between a ligand ( Drug ) and its binding site. It is a structure based technique which attempts to find the best match between two molecules. 3

4. TYPES OF MOLECULAR DOCKING RIGID DOCKING FLEXIBLE DOCKING EXTRA PRECISION DOCKING MANUAL DOCKING 4

5. RIGID DOCKING/ LOCK & KEY DOCKING Both the ligand and receptor molecules are regarded as rigid bodies . No conformational changes are allowed. Features: Fixed Conformations Limited Flexibility Fast and Efficient 5

6. STEPS FOR RIGID DOCKING 6 INPUT PREPARATION Target Selection Ligand Selection Structure Cleaning RECEPTOR & LIGAND FIXATION Ligand kept rigid Receptor kept rigid IDENTIFY THE ACTIVE SITE

7. 7 DOCKING ALGORITHM APPLICATION SCORING FUNCTION EVALUATION RANKING OF POSES Best poses selected based on lowest energy OUTPUT & ANALYSIS Top ranked docked poses selected for further evaluation

8. Advantages Speed Simplicity Suitable for Larger structures Disadvantages Lack of flexibility Lower accuracy Misses potential interactions Softwares DOCK, FLOG, FTDOCK 8

9. FLEXIBLE DOCKING/ INDUCED FIT DOCKING Atleast one of the molecules is allowed to flexible. Based on flexibility- Types Flexible ligand and rigid receptor docking Flexible ligand and flexible receptor docking 9

10. STEPS FOR FLEXIBLE DOCKING 10 INPUT PREPARATION Target Selection Ligand Selection Structure Cleaning DEFINE FLEXIBILITY Assign ligand rotatable bonds. Identify flexible regions in the receptor IDENTIFY THE ACTIVE SITE

11. 11 DOCKING ALGORITHM APPLICATION SCORING FUNCTION EVALUATION RANKING OF POSES Best poses selected based on lowest energy OUTPUT & ANALYSIS Top ranked docked poses selected for further evaluation

12. Key featues Ligand flexibility Receptor flexibility Exploration of conformational space Advantages Higher accuracy Realistic modelling Discovery of novel interactions Mimics experimental findings Disadvantages High computational expense Scoring function limitations Lower success rates Softwares AutoDOCK Glide DOCK 12

13. EXTRA PRECISION DOCKING/ XP DOCKING It is a module available in schrodinger unit. The purpose is to rule out false positives and to provide a better correlation between good poses and good scores. It is employed to refine and optimize docking results. Provide more reliable predictions of ligand- receptor interactions Only top scoring ligands should be docked using XP mode. 13

14. STEPS FOR EXTRA PRECISION DOCKING 14 INPUT PREPARATION PREPARE BINDING SITE INITIAL DOCKING (STANDARD PRECISION) EXTRA PRECISION (XP) DOCKING SCORING & RANKING POST-DOCKING MINIMIZATION OUTPUT & ANALYSIS

15. Adantages Higher accuracy Reduced false positives Better handling of flexibility Disadvantages High computational cost Not an universal solution Reliance on high quality protein structure 15

16. MANUAL DOCKING It is a hands on approach to molecular docking Here manually positions to ligand in the binding site This involves directly placing and adjusting the ligand within the receptor active site using molecular visualization software 16 Softwares PyMOL , AutoDOCK Tools, Discovery Studio

17. STEPS FOR MANUAL DOCKING 17 INPUT PREPARATION Target Selection Ligand Selection Structure Cleaning IDENTIFY BINDING SITE MANUAL PLACEMENT OF LIGAND

18. 18 OPTIMIZE POSITIONING ENERGY MINIMIZATION SCORING & EVALUATION OUTPUT & ANALYSIS

19. STUDY USING MOLECULAR DOCKING Synthesis, Molecular Docking Studies, and Evaluation of Antibacterial and Antioxidant activities of Pyrazoline derivatives   Mohammed et al . (2024) conducted studies on pyrazoline derivatives, pyrazoline derivatives 6 and 9 were screened for their  antibacterial activity  against two Gram-negative bacteria (E. coli and P. aeruginosa ) and two Gram-positive bacteria (S. aureus and S. pyogenes ).   Molecular docking study of the synthesized derivatives was conducted to evaluate their binding pattern with human  myeloperoxidase  and S. aureus gyrase . The in- silico interaction results aligned with the in vitro analysis of the synthesized compounds and demonstrated well against S. aureus gyrase (PDB ID 2XCT ) and    human myeloperoxidase (PDB ID 1DNU) 19

20. 20 Molecular docking results of novel synthesized compounds against S. aureus gyrase (PDB ID 2XCT).   Molecular docking results of novel synthesized compounds against human myeloperoxidase (PDB ID 1DNU). Derivative Ligands Binding Affinity (kcal/ mol ) 6 C 21 H 17 N 3 O 2 – 10.1 9 C 21 H 17 N 3 O 3 – 10.2 Ciprofloxacin C17H18FN3O8 −8.4 Derivative Ligands Binding Affinity (kcal/ mol ) 6 C 21 H 17 N 3 O 2 – 9.4 9 C 21 H 17 N 3 O 3 – 9.6 Ascorbic Acid C 6 H 8 O 6 – 8.1

21. REFERENCES Bharathwaj J, Deepak Venkataraman N, Charumathi P, Lakshminarasimman S, Purushothaman VM, Sudharsan S. An Overview of Basics, Types, Approaches, Applications, Advantages and Disadvantages of Docking. Int J of Pharm Sci. 2025;3:437–45 . Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem . 1998;19(14):1639–62 . Morris RJ, Najmanovich RJ, Kahraman A, Thornton JM. Real spherical harmonic expansion coefficients as 3D shape descriptors for protein binding pocket and ligand comparisons. Bioinformatics . 2005;21(10):2347–55 . 21

22. Kahraman A, Morris RJ, Laskowski RA, Thornton JM. Shape variation in protein binding pockets and their ligands. J Mol Biol . 2007;368(1):283–301.  Mohammed N, Mulugeta E, Garg A, Tadesse A. Synthesis, molecular docking Studies, and evaluation of antibacterial and antioxidant activities of pyrazoline derivatives. Results in Chemistry. 2024;8: 290-302. Suresh PS, Kumar A, Kumar R, Singh VP. An insilico approach to bioremediation: laccase as a case study. J Mol Graph Model . 2008;26(5):845–9 . 22

23. 23