Introductory Chapter: Molecular Docking and Molecular Dynamics Techniques to Achieve Rational Drug Design

*Amalia Stefaniu*

Molecular docking and molecular mechanics simulations are important approaches to achieve a rational drug design or a chemical process modeling. It goes to deep molecular insights as structures and mechanisms helping researchers to characterize various conformations and molecular interactions in terms of energy and binding affinities, giving the possibility to search among dozens, hundreds of real or imaginary compounds, the most suitable for a precise, well-defined purpose. The biochemical purpose derives from the chosen macromolecular target, protein, or enzyme. Starting from a known substance with a known mechanism of action and biological activity, we can imagine other related compounds as drug candidates with better efficacy and fewer side effects. These in silico methods help us to identify and select among large compound libraries the most suitable therapeutic agent before even starting its chemical synthesis. That can be called virtual chemistry before reaction tube. It is very convenient, reducing the consumption of chemical reagents, preclinical, clinical trials, and time.

The purpose of this book project is to clearly explain the principles of molecular docking and molecular dynamics, with examples of algorithms and procedures proposed by different software programs for small molecule-protein or protein-protein complexes of medical or materials sciences interest.

Molecular docking studies provide us an overview of type of interactions occurring in ligand (small molecule)-protein or protein-protein complexes and rank the candidate poses by their affinity scoring function.

The concept of molecular recognition of ligand at the protein/enzyme active site, classically named "lock and key," has been extended at "hand and glove," considering the protein flexibility and reciprocal adaptability between the receptor and ligand [1].

Molecular dynamics simulations explore extrinsic surface and bulk properties of various forms of pharmaceutically active molecules to aid the selection of a successful candidate. It involves accurate evaluation of binding pathways, kinetics, and thermodynamics of ligands in different solvents.

Both these computer-aided drug design (CADD) methods lead to ligand identification and optimization, favoring rapid development of pharmaceutical compounds.

## **1. Molecular docking approaches and challenges**

Different software algorithms use various approaches such as rigid protein or flexible protein, rigid receptor, soft receptor, flexible side chains, induced fit, or multiple structure algorithms [2].

The steps for conducting molecular docking studies are:


Protein Data Bank (https://www.rcsb.org/) provides various solved 3D structures of protein, protein fragments, nucleic acids, and protein-ligand complexes. The assemblies are characterized by X-ray crystallography, nuclear magnetic resonance (NMR), infrared spectroscopy, and or/electron density and are available as PDB files format. This online tool allows us to explore and analyze the structures or to compare any protein in the PDB archive, including support for rigid-body and flexible alignments.

Also, for simulation the optimized ligand structure must be imported and used in the docking software as \*.pdb or compatible file.


Pharmaceutical applications

• Exploring DNA binding properties of some malignant tumor chemotherapeutic agents [4–7] (to identify the DNA binding site, to predict interactions between potential therapeutic compound and DNA, to assess the stability of DNA-complexes, and to establish correlations between structure and cytotoxicity).

**3**

**Author details**

Amalia Stefaniu

Romania

provided the original work is properly cited.

\*Address all correspondence to: astefaniu@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

National Institute for Chemical, Pharmaceutical Research and Development,

*Introductory Chapter: Molecular Docking and Molecular Dynamics Techniques to Achieve…*

• In silico modeling as attempts to find new efficient therapeutic compounds against pathogens, causative agents of infectious disorders, antitubercular drugs [8–11], antibiotics agents against Escherichia coli [12–14], Pseudomonas aeruginosa [14–16], Staphylococcus aureus [13, 14, 16–19], Bacillus cereus

The computational findings must be completed and confirmed by biological assays to determine in vitro activity, by measuring minimum inhibitory concentra-

Molecular dynamics (MD) simulations are useful approaches when analysis of thermodynamic and kinetic properties of ligand-binding events is required to consider. Besides, MD has become effective tools used to modeling chemical processes and to evaluating different parameters of materials in different media (water or gas): velocity direction of removal of material electrical discharge machining (EDM) [20], indentation [21], wear and friction [22], nano-cutting [23], and laser

*DOI: http://dx.doi.org/10.5772/intechopen.84200*

tion against tested microorganisms.

machining [24].

[13, 16], Klebsiella pneumoniae [13], or others.

*Introductory Chapter: Molecular Docking and Molecular Dynamics Techniques to Achieve… DOI: http://dx.doi.org/10.5772/intechopen.84200*

• In silico modeling as attempts to find new efficient therapeutic compounds against pathogens, causative agents of infectious disorders, antitubercular drugs [8–11], antibiotics agents against Escherichia coli [12–14], Pseudomonas aeruginosa [14–16], Staphylococcus aureus [13, 14, 16–19], Bacillus cereus [13, 16], Klebsiella pneumoniae [13], or others.

The computational findings must be completed and confirmed by biological assays to determine in vitro activity, by measuring minimum inhibitory concentration against tested microorganisms.

Molecular dynamics (MD) simulations are useful approaches when analysis of thermodynamic and kinetic properties of ligand-binding events is required to consider. Besides, MD has become effective tools used to modeling chemical processes and to evaluating different parameters of materials in different media (water or gas): velocity direction of removal of material electrical discharge machining (EDM) [20], indentation [21], wear and friction [22], nano-cutting [23], and laser machining [24].
