Using Molecular Modelling to Study Interactions Between Molecules with Biological Activity
María J. R. Yunta · Bioinformatics · 2012
Computational methods have become increasingly important in a number of areas such as comparative or homology modelling, functional site location, characterisation of ligandbinding sites in proteins, docking of small molecules into protein binding sites, proteinprotein docking, and molecular dynamic simulations [see for example Choe & Chang, 2002].Current results yield information that is sometimes beyond experimental possibilities and can be used to guide and improve a vast array of experiments.To apply computational methods in drug design, it is always necessary to remember that to be effective, a designed drug must discriminate successfully between the macromolecular target and alternative structures present in the organism.The last few years have witnessed the emergence of different computational tools aimed at understanding and modelling this process at the molecular level.Although still rudimentary, these methods are shaping a coherent approach to help in the design of molecules with high affinity and specificity, both in lead discovery and in lead optimisation.Moreover, current information on the 3D structure of proteins and their functions provide a possibility to understand the relevant molecular interactions between a ligand and a target macromolecule.As a consequence, a comprehensive study of drug structure-activity relationships can help identify a 3D pharmacophore model as an aid for rational drug design, as a pharmacophore model can be defined as 'an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response', and a pharmacophore model can be established either in a ligandbased manner, by superposing a set of active molecules and extracting common chemical features that are essential for their bioactivity, or in a structure-based manner, by probing possible interaction points between the macromolecular target and ligands.Molecular recognition (MR) is a general term designating non-covalent interactions between two or more compounds belonging to host-guest, enzyme-inhibitor and/or drug-receptor complexes.A rigorous approach to an MR study should involve the adoption of a computational method independent from the chemical intuition of the researcher.Drug design purposes prompt another challenging feature of such an ideal computational method, the ability to make sufficiently accurate thermodynamic predictions about the recognition process. Molecular modelling methods and their usefulnessMolecular recognition is a central phenomenon in biology, for example, with enzymes and their substrates, receptors and their signal inducing ligands, antibodies and antigens, among others.Given two molecules with 3D conformations in atomic detail, it is important to know if the molecules bind to each other and, if it is so, what does the formed complex look like ("docking") and how strong is the binding affinity (that can be related to the "scoring"functions).Molecules are not rigid.The motional energy at room temperature is large enough to let all atoms in a molecule move permanently.That means that the absolute positions of atoms in a molecule, and of a molecule as a whole, are by no means fixed, and that the relative location