Computational Aspects of Drug Design

What is drug discovery?

We can say that Drug Discovery is a process in which researchers design or discover novel chemical compounds that can act like drugs. Nowadays, scientists use various computational methods for drug discovery. By using these methods, we have reduced both time and cost involved in drug discovery work. This is because Computer-Aided Drug Design (CADD) methods drastically reduce the total number of compounds to be screened against the disease. The use of CADD methods is also labour efficient. Synthesis and biases are always laborious and the chance of getting false positives is always present after spending lots of physical and mental labour in finding a suitable drug.

We start our journey by going to a protein data bank to choose our protein of interest. Protein Data Bank is a repository of crystal core structures that are experimentally solved by NMR spectroscopy or X-ray crystallography. There are different types of computational methods that we can use for the prediction of the structure of the target protein. Some of them are homology modelling, threading and ab initio modelling.

After finalising our protein we need to find the binding site so that the ligand of interest can go and bind to it. The dynamic nature of biomolecules sometimes makes it insufficient to use a single static structure to predict proper binding sites. What molecular dynamics does is, it generates multiple confirmed confirmations of our target protein that will be used for identification of the binding site. We will be looking at this in more detail in the upcoming portions of the article. Next prerequisite will be to have a mathematical description that we use to model and predict how atoms or molecules interact with each other at the atomic and molecular level.

Different Representations of the SARS-CoV super complex of non-structural proteins: the hexadecamer. These are what PDB files look like!

Molecular dynamics is a computational method that uses Newton's equations of motions to study movements of molecules. To quote from Springer’s “Molecular dynamics (MD) is a computational tool to simulate the motions of a molecular system. The method requires an interaction potential from which interatomic forces can be calculated and equations of motion that govern the dynamics of the system. Originally developed to study properties of the liquid state, MD simulations are nowadays routinely applied to macromolecular systems of biological and pharmaceutical interest.”