Question

1. Suppose you modify a ligand to increase its ability to hydrogen bond with residues in the protein’s active site. Will this increase the binding affinity of that ligand to the protein. Explain your answer.

2. Describe how you know if a molecule is a bad choice for a substrate from PyRx results. Include one structural and one free energy argument.

Answer 1

Introduction: Docking is a molecular modeling technique that helps to understand structure-function relation, identify the binding site in a target molecule and to predict the binding ability of a molecule. The study of many molecular structures such as protein, enzyme and drugs that fit together is termed as molecular docking. Its application is common in the field of drug designing and discovery.

Binding affinity of that ligand to the protein

A ligand is termed as a molecule which binds to a central molecule forming a coordination complex. Examples of ligands include water (H2O), chloride (Cl-) and ammonia (NH3). The ligand bonding can occur because it may act as donor or acceptor. In ligand- protein binding, the ligand produces a signal by binding on a specific site of a target protein. The binding affinity is the strength of interaction between ligand binding on the specific site of a target protein.

Hydrogen bond is a strong bond that tightly holds macromolecules such as proteins and DNA. Hydrogen bonding is formed when water and ligand competes with other for bonding sites. The hydrogen bonding is an exchange reaction wherein hydrogen donors or acceptors of a free protein and ligand molecule break their link with water so that new hydrogen bonds are formed between protein and ligand molecule. Thus binding affinity of a ligand to protein increases by modifying the ligand to increase its ability to hydrogen bonding.

PyRx analysis

Virtual screening software used for drug discovery is PyRx. It involves computational screening that of compounds from libraries against several potential drug targets. It is docking software that is user friendly. A screening procedure cannot identify the compounds with a high activity but based on hit-to-lead and lead optimization stages the binding ability of diverse compounds can be predicted. PyRx is commonly used for analyzing several small molecules from libraries having low binding energies. An example is purine-based analogues. PyRx can compute free binding enthalpies using docking and simulations which is applicable for protein-ligand systems. Docking software such as PyRx predicts the activity of ligand compounds based on the score. The score does not predict the binding affinity of compounds. Compounds that have similar structures exhibit similar properties with similar effects. Thus it is a drawback in virtual screening.