Molecular Docking

 

Molecular Docking

Molecular recognition is the ability of biomolecules to recognize other biomolecules and selectively interact with them in order to promote fundamental biological events such as transcription, translation, signal transduction, transport, regulation, enzymatic catalysis, viral and bacterial infection and immune response.

Molecular docking is the process that involves placing molecules in appropriate configurations to interact with a receptor. Molecular docking is a key tool in structural molecular biology and computer-assisted drug design. Docking is computational simulation of a candidate ligand binding to a receptor.

In molecular modeling the term “molecular docking” refers to the study of how two or more molecular structures fit together. Molecular docking is the process that involves placing molecules in appropriate configurations to interact with a receptor. Molecular docking is a natural process which occurs within seconds in a cell when bound to each other to form a stable complex. Docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation is used to predict the strength of association or binding affinity between two molecules using scoring functions. The associations between biologically relevant molecules such as proteins, nucleic acids carbohydrates, and lipids play central role in signal transduction. Therefore docking is useful for predicting both the strength and type of signal produced. Docking is frequently used to predict the binding orientation of drug candidates to their protein targets in order to predict the affinity and activity of the small molecule. Hence docking plays an important role in the rational design of drugs. The aim of molecular docking is to achieve an optimized conformation for both the protein and ligand and relative orientation between protein and ligand so that the free energy of the overall system is minimized. The goal of ligand-protein docking is to predict the predominant binding mode(s) of a ligand with a protein of known three-dimensional structure. 

 

 

 

Docking usually occurs  between

·         Protein – Ligand

·         Protein – Protein

·         Protein – Nucleotide

                              

TYPES OF DOCKING

There are 2 types of docking

1. Rigid docking

2. Flexible docking

 

1 .Rigid Docking

If we assume that the molecules are rigid, then we are looking for a transformation in 3D space of one of the molecules which brings it to an optimal fit with the other molecules in terms of a scoring function. The ligand’s conformation can be formed with or without receptor binding activity.  In rigid-body docking, the search space is restricted to three rotational and three translational degrees of freedom. The rigid-body docking approaches are often not sufficient to predict the structure of a protein complex from the separate unbound structures.

2. Flexible Docking

In conjunction with transformation, we evaluate molecular flexibility to identify confirmations for the receptor and ligand molecules as they exist in the complex. The incorporation of molecular flexibility into docking algorithms requires to add conformational degrees of freedom to translations and rotation. Approximation algorithms need to be introduced to reduce the dimensionality of the problem and produce acceptable results within a reasonable computing time

 

Models of molecular docking

 

 

 

1.      The Lock and Key Theory

In  1890, Emil Fischer proposed a model called the "lock-and-key model" as shown in figure  states that explained how biological systems function. A substrate fits into the active site of a macromolecule, just like a key fits into a lock. Biological locks have unique stereochemical features that are necessary to their function

2.      The Induced-Fit Theory

 In 1958, Daniel Koshland introduced the "induced fit theory". The basic idea is that in the recognition process, both ligand and target as shown in figure mutually adapt to each other through small conformational changes, until an optimal fit is achieved.

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3.       The Conformation Ensemble Model

 In addition to small induced-fit adaptation, it has been observed that proteins can undergo much larger conformational changes. A recent model describes proteins as a pre-existing ensemble of conformational states. The plasticity of the protein allows it to switch from one state to another

Experimental techniques for study molecular recognition include X-ray crystallography, NMR, electron microscopy, site directed mutagenesis, co-immuno-precipitation etc... They allow us to experimentally solve the detailed 3‑dimensional structures of biomolecules in their association form which is a necessary step in identifying crucial residues, study the strength of interaction forces, their energetics, understand how molecular structures fit together, and investigate mechanisms of action.

 

Factors affecting docking

·         Intramolecular forces.

1.      -bond length

2.      -bond angle

3.      -dihedral angle

·         Intermolecular forces

1.      -electrostatic

2.      -dipolar

3.      -H-bonding

4.      -hydrophobicity

5.      -Vander waals forces

Key stages in docking

·         Target/Receptor selection and preparation

·         Ligand selection and preparation

·         Docking

·         Evaluating docking results

 

 

 

 

 

 

 

MOLECULAR DOCKING APPROACHES

 There are number of approaches exist for docking as follows

 Monte Carlo Approach: It generates an initial configuration of a ligand in an active site consisting of random conformation, translation & rotation. It scores initial configuration. Then it generates new configuration & score it. It use Metropolis criterion to determine whether the new configuration is retained. (Metropolis criterion- If new solution scores better than the previous one, it is immediately accepted. If the configuration is not new one, a Boltzmann-based probability function is applied. If the solution passes the probability function test, it is accepted; if not the configuration is rejected).

Fragment based method: Fragment based methods can be described as dividing the ligand into separate protons or fragments, docking the fragments & finally linking these fragments together.

Distance Geometry: Many types of structural information can be expressed as intra or intermolecular distances. The distance geometry formalism allows these distance to be assembled & 3 dimensional structures consistent with them to be calculated.

 

Matching approach: These approach focus on complimentarity. Ligand atom is placed at the „best‟ position in the site, generating a ligand receptor configuration that may require optimization

Ligand fit approach: Ligand fit term provide a rapid accurate protocol for docking small molecules ligand into protein active sites for considering shape complimentarity between ligand & protein active sites

Point Complimentarity approach: These methods are based on evaluating a shape & /or chemical complimentarity between interacting molecules.

 Blind Docking: It was introduced for detection of possible binding sites & modes of peptide ligand by scanning the entire surface of protein targets.

 Inverse Docking: In this use of a computer method for finding toxicity & side effect protein targets of a small molecule. Knowledge of these targets combined with that of proteomics pharmacokinetic profile can facilitates the assessment of potential toxicities side effect of drug candidate. One of these protocols is selected for docking studies of particular ligand.

Requirements for molecular docking

 A ligand docking strategy involves the following elements: a target protein design, the compounds of interest or a database comprising existent or virtual compounds for the docking process, and a computational foundation that enables the appropriate docking and scoring methods to be implemented.  The majority of docking algorithms consider the protein to be stiff, whereas the ligand is often considered to be flexible. Apart from the structural degree of freedom, the bonding position of the protein in its binding pocket must be considered. Docking of solid molecules or segments onto the active site of a protein can be accomplished in a variety of ways, including consensus search, geometric hashing, and pose clustering.

 

 Ligand representation

Commonly, the configuration with the highest probability of becoming predominant is further weaked by adding or deleting hydrogen atoms to obtain estimated pKa values. It is critical that precise atomic coding transpires.

Receptor representation

 The integrity of the receptor structure used is critical for the effectiveness of docking simulations. Overall, the greater the resolution of the crystal lattice used, the greater the docking findings seen. A recent study of the accuracy, limits, and hazards of ligand-protein complex structure refinement techniques, in general, provides a rigorous analysis of the known structures.

Applications of molecular docking

Docking is most often employed for drug discovery, as the majority of medications are composed of tiny organic compounds.

Hit identification

Docking in conjunction with a score function enables rapid screening of vast databases of possible medications in silico to find compounds that are capable of binding to a particular target of interest.

Lead optimization

 Docking can be used to anticipate the location and relative position of a ligand’s interaction to a protein (also referred to as the binding mode or pose).  This data can be utilized to develop more powerful and selective analogues.

Remediation

Additionally, protein-ligand docking may be utilized to forecast which contaminants are degradable by enzymes. It can be utilized for the determination of the desired location, collection of the most effective medication.

Molecular docking can be used to identify enzymes and their mode of action. It can also be utilized to determine relationships between proteins. Molecules are screened virtually by using the remediation method.

Application of molecular modeling in modern drug development

 It is used to evaluate for potential harms produced by relationships with other proteins, such as proteases, cytochrome P450, and others. Docking can also be used to determine the specificity of a proposed medication against homologous proteins. Additionally, docking is a frequently utilized technique for identifying protein-protein interactions.  Comprehension of cellular connections helps in the comprehension of a range of processes occurring in live organisms and the identification of potential pharmaceutical targets

 

Software available for docking

 Gold

Genetic Optimisation and Ligand Docking, make use of numerous ligand subgroups. Three terms comprise the force-field-based scoring function: The phrase "H-bonding" refers to the potential for intermolecular dispersion. The word "intramolecular potential" refers to the potential for intramolecular dispersion.  71% success rate in determining the experimental binding mode for 100 protein complexes.

Autodock

Consists of a three-dimensional lattice of regularly spaced points encircling and cantered about the macromolecule’s region of interest.

Flex-X

Using the "position clustering" technique, the base fragment is picked up and docked. A clustering approach is used to combine related ligand changes into active site modifications.  Flexible fragments are sequentially added using MIMUMBA and assessed using the overlap function, followed by energy calculations to finish the ligand construction.  Final assessment using Böhm’s scoring system, which incorporates hydrogen bonds, ionic, aromatic, and lipophilic terms.

 There is several other software are available for docking such as Hammerhead, ICM, MCDock, GOLD, GemDock, Glide and Yucca.

AVAILABLE SOFTWARES FOR DOCKING

 · DOCK (1982,2001)

· FleX (1996)

· Hammerhead (1996)

· Surflex (2003)

· SLIDE (2002)

· AutoDock (1990,1998)

· ICM (1994)

 · MCDock (1999)

· GOLD (1997)

· GemDock (2004)

 · Glide (2004)

· Yucca (2005 )

—         CB DOCK (Onine)