1. Research Techniques Made Simple: Molecular Docking in Dermatology – A Foray Into In Silico Drug Discovery
Naiem T. Issa, MD, PhD1, Evangelos V. Badiavas, MD, PhD1, Stephan Schurer, PhD2
1Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine 2Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine

2. Fundamentals of Docking
(1) Docking is the computational modeling of how drugs (ligands, L) can occupy and interact with protein target (P) binding sites. 
(2) Predictions based on approximating the free energy of binding (ΔG). The greater (more negative) the ΔG, the greater the stability of the ensuing complex (PL) and the more likely its formation 

3. Docking Process in Virtual Screenings
(1) Docking algorithm takes virtual library of drug molecules and determines how each may fit in the target protein's binding site. (2) Drug molecules are ranked based on predicted free energy of binding (ΔG) - the more negative ΔG, the more highly ranked the drug.

4. Utility of Molecular Docking
Screen very large drug libraries against protein target of interest to prioritize for efficient biological testing (virtual screening).
>10,000,000 molecule database
<100 molecules for in vitro testing
Docking Algorithm
Structure of protein target

5. Utility of Molecular Docking
Predict drug mechanism(s) of action at protein target binding site.
Docking with Ligand Interaction Diagram
How does it bind?

6. Utility of Molecular Docking
Screen drug of interest against hundreds of protein targets to predict off-target effects (inverse docking)

7. Generalized Docking Protocol
(1) Three major components required prior to docking: protein target model, identification of potential binding site, ligand(s) (2) Protein target and ligand(s) must be modeled in 3D at appropriate pH. This is critical for assigning appropriate protonation states of functional groups. (3) Ligand(s) docked into putative binding site using software of choice and ranked based on docking score (e.g. free energy of binding, ΔG)
**A detailed protocol for beginners can be
found in Forli et al. Computational protein
-ligand docking and virtual drug screening
with the AutoDock suite. Nat Protoc.
2016; 11:  

8. Important Considerations
Multiple docking algorithms and scoring functions exist – choice affects outcomes
Docking performed in a vacuum – lack of physiologic solvent and ion content 
Significant false positive rate due to simplification of biological system
Inverse relationship between computational cost/time and accuracy
Post-docking energy calculation refinements with MM-GBSA/PBSA methods that include solvent, ions and other biophysical parameters to increase true positive rate

9. Important Considerations
Docking considers single "snapshot" of molecular interaction
Biological systems in flux (interactions change over time)
Molecular Dynamics (MD) allows for such study of atomic interactions over time
MD simulations require heavy graphical processing (GPUs)

10. Summary Points
(1) Computational molecular modeling tools aid in drug discovery to increase accuracy and expedite preclinical hit and lead identification.
(2) Docking is the computational modeling of how drugs can occupy and interact with protein target binding sites. 
(3) Docking aids in narrowing the potential chemical (drug) space from tens or hundreds of millions of compounds to tens or hundreds for efficient biological testing and validation.
(4) Open source software for molecular modeling and docking are freely available for academicians to use in their investigations.