Category: Molecular Docking Training & Certification- Self Learning Course

Molecular Docking can be defined as the computer-aided prediction of the confined geometry of two or more molecules. In simple terms, docking means the attempts to find the “best” matching between two molecules. Molecules may be docked automatically by using computer algorithms or manually with the aid of computer graphics and is done using molecular visualization software. Molecular docking involves the interaction of two or more molecules to give stable adduct and is a kind of bioinformatic modeling.

In the field of molecular modeling, when molecules bound to each other to form a stable complex, the preferred orientation of one molecule to another can be predicted using the molecular docking method. The strength of association or binding affinity between two molecules can be in turn predicted with the knowledge of the preferred orientation.

Types of Docking:

• Rigid Docking (Lock and Key)
• Flexible Docking (Induced Fit)

Docking can be done between:

• Protein-Ligand
• Protein-Protein
• Protein-Nucleotide

Docking depends on two main components:

1. Scoring function: Scoring function predicts the strength of interactions between two molecules after they are docked.
2. Genetic Algorithm: Genetic algorithm is one of the conformational searches and it gives scoring functions for each pose of the ligand.

 

Fig:  Methods used for protein-ligand docking 

Aim of Molecular Docking

Providing a prediction of the ligand-receptor complex structure using computational methods is the aim of molecular docking. The molecular docking approach allows us to characterize the behavior of small molecules in the binding site of target proteins as well as to elucidate fundamental biochemical processes as it can be used to model the interaction between a small molecule and a protein at the atomic level. Two basic steps are involved in the docking process: prediction of the ligand conformation as well as its position and orientation within these sites (usually referred to as pose) and assessment of the binding affinity. Through two interrelated steps, docking can be achieved:

1. By sampling conformations of the ligand in the active site of the protein;
2. Ranking these conformations via a scoring function.

Docking predicts the three-dimensional structure of any complexity, depending upon binding properties of ligand and target. A scoring function in the software is used to rank and group together the different possible adduct structures generated by molecular modeling. Ideally, the experimental binding mode should be reproduced through sampling algorithms and the scoring function should also rank it highest among all generated conformations.

Docking methods combine and optimize variables such as hydrophobic, steric, and electrostatic complementarity and also estimate the free energy of binding (scoring) to fit a ligand into a binding site.

Why is Molecular Docking Important?

Molecular docking is of extreme relevance in cellular biology, where proteins interact with themselves and with other molecular components in order to accomplish a function. Docking is useful in signal transduction, the strength and the type of signals produced by the associations between biologically relevant molecules such as lipids, carbohydrates, nucleic acids, and proteins, can be predicted.

Docking plays a crucial role in drug design. To predict the binding orientation of small molecule drug candidates to their protein targets, docking is frequently used so that the affinity and activity of the small molecule can be predicted. Thus, in the rational design of drugs, docking plays an important role.

Molecular docking suggests the binding modes responsible for inhibition of the protein and it helps us in predicting the intermolecular framework formed between a protein and a small molecule or a protein and protein.

Softwares Used in Molecular Docking

Using NMR, the high-resolution X-ray, or homology-modeled structure with known/predicted binding sites in the biomolecule, one can accurately carry out docking studies.

Depending on the types of docking, the Softwares used vary. In protein-protein docking, Softwares include Autodock, Affinity, Vega, Situs, Ligplot, Gold, Glide, Flex-X, Flexidock, Fred, Dockvision, and Combibuild. In protein-ligand docking, Softwares include Patch Dock, ICM-Dock, Gramm, and Dock. In Protien-Protien & Protien-Ligand docking, Softwares include Dot (Daughter Of Turnip), 3d-Dock Suite, Cluspro, Bigger, Hex, Haddock, and Bielefeld Protein Docking. Other Common Softwares used for docking include UCSF DOCK, AUTODOCK, FlexX, GOLD, AADS, ADAM, DARWIN, DIVALI, BetaDock, DockVision, EADock.

Applications of Molecular Docking

The feasibility of any biochemical reaction can be demonstrated by molecular docking. Some areas have been revolutionized by molecular docking. Some of the major applications of molecular docking include:

-Drug Discovery (Lead optimization)

Molecular modeling and molecular docking methods can be utilized to accelerate the drug discovery process for getting new drug molecules. An optimized orientation of ligand on its target can be predicted by molecular docking. Different binding modes of a ligand in the groove of the target molecule can be predicted. More efficient, selective, and potent drug candidates can be developed using this.

-Virtual Screening (Hit identifications)

To identify molecules that are likely to bind to a protein target of interest, docking with a scoring function can be used to quickly screen large databases of potential drugs in silico.

-Drug-DNA interaction

In the initial prediction of the drug’s binding properties to the nucleic acid, molecular docking plays a prominent role. The correlation between the drug’s molecular structure and its cytotoxicity is established with this information. By investigating the interaction mode between nucleic acid and drugs in the presence of copper, medicinal chemists are constantly putting their efforts to elucidate the underlying anticancer mechanism of drugs at the molecular level. To predict whether the compound/drug is interacting with the protein/DNA, they are doing in silico observations. The experimental procedures are made available to find out the real binding mode of the complex if the docking program is predicting the said interaction. New anticancer drugs can be developed through this.

-Bioremediation

Pollutants that can be degraded by enzymes can also be predicted using protein-ligand docking.

Molecular Docking Career Prospects

Given the rapid development of the field and the use of modern drug designing, there is a vast array of jobs in the field of Molecular Docking.

The basic eligibility to have a career in molecular docking would be undergraduate level degree and above, along with conceptual certification courses. Higher-level jobs require previous experience in applying molecular modeling methods to structure, ligand and fragment-based drug discovery projects, ADME modeling and drug ADME profile optimization, a certain degree of proficiency in programming/scripting, working knowledge of databases, etc.

Candidates are expected to have good knowledge in data interpretation of NMR, Mass, HPLC, and GC. A candidate with the required qualification, knowledge, and skillset, can have a successful career in molecular docking, working as a:

• Structural Biologist
• Computational Chemist
• Computational Drug Discovery Scientist
• Scientist – Molecular Modeler/ Molecular Pharmaceutics/ Protein Engineering/ Structure-Based Antibody Modeling/ Modeling & Simulation Scientist
• Computational Biophysics And Data Analyst
• Scientific Software Developer
• Project Assistant
• Research Associate
• Research Technician
• Bioinformaticist
• Professorship