Chemistry Reference
In-Depth Information
CHAPTER 3
General Aspects of Molecular Interaction Fields in Drug Design
Vinicius Barreto da Silva, Jonathan Resende de Almeida and Carlos Henrique Tomich de
Paula da Silva
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Monte Alegre,
14040-903, Ribeirão Preto, São Paulo, Brazil
Abstract:
Computational techniques are effective tools for aiding the drug design process. Computational
chemistry can be used to predict physicochemical properties, energies, biding modes, interactions and a wide
amount of helpful data in lead discovery and optimization. The interactions formed between a ligand and a
molecular target structure can be represented by molecular interaction fields (MIF). The MIF identify regions of a
molecule where specific chemical groups can interact favorably, suggesting interaction sites with other
molecules. In this context the MIF theory has been extensively used in drug discovery projects with a variety of
applications, including QSAR, virtual screening, prediction of pharmacokinetic properties and determination of
ligand binding sites in protein target structures.
INTRODUCTION
One of the challenges for the health sciences scientific community is the search for new and effective drugs in order
to provide better treatments for patients that are suffering from diseases that affect mankind. Today, the field of drug
development deals with a large amount of data generated from information provided by new genomic and proteomic
techniques. In this way, new attractive and potential pharmacological targets are discovered and there is a need to
rationalize the application of methods to transform these data to knowledge and introduce new drugs in clinical
protocols for effective treatments.
A fundamental postulate in the classical drug design paradigm is the fact that the effect of a drug in the human body
is a consequence of the molecular recognition between a ligand (the drug) and a macromolecule (the target).
Structure-based drug design plays a central role in this field of research since the pharmacological activity of the
ligand at its site of action is related to the spatial arrangement and electronic nature of the atoms of the ligands as
well as how these atoms interact with their biological counterparts. Computational chemistry can be used to
characterize the dynamics and energetics of such interactions and yield insights in molecular recognition processes
in order to better rationalize drug design [1-9].
The available drugs available interact with their molecular targets via non-covalent interactions. Under this
assumption, one of the main interests of computational chemistry is to develop methods, applying molecular
recognition concepts, that could predict protein-ligand interactions in order to predict conformation and affinity of
small molecules with molecular targets [10]. In this way new ligands can be obtained guiding the search for
effective drugs. Computational chemistry can be applied to help in the other stages of drug design as well, i.e
optimization of pharmacokinetic properties and prediction of toxicity data [11-16 ].
Molecular recognition is of central importance in biological processes. H-bonding, stacking, ionic and hydrophobic
interactions are normally observed in ligand-protein complexes [17]. In order to understand the contribution of each
interaction and the basis of biological functions in a particular biological or pharmacological process, the knowledge
of molecular electrostatic potentials is critically important. In principle, interaction forces are composed of three
components: electrostatic, inductive and dispersive [18].
The electrostatic interaction is characteristic of polar molecules, which carry a charge or a permanent dipole
moment. The inductive forces are relevant when a polar molecule interacts with a non-polar molecule. In this way,
the dipole of the polar molecule produces an electric field that changes the electronic distribution of the non-polar
molecule inducing a dipole moment. When the interacting molecules are non-polar there are dispersion forces,
