Chemistry Reference
In-Depth Information
hydrophobic surface exposed by the compound to the environment that is related to the lipophilicity. This is a
parameter that can be used to predict solubility and membrane permeation, for example [28].
Another approach based on 3D molecular fields is the Volsurf procedure. The method produces 2D molecular
descriptors from 3D molecular field maps. Volsurf descriptors are specifically designed to optimize pharmacokinetic
properties. The Volsurf descriptors encode physico-chemical parameters allowing the study of quantitative structure-
property relationships (QSPR), which are developed in the physical-chemical property space intending to modulate
pharmacokinetic profiles [45]. These descriptors can be quantitatively compared and used to build multivariate
models correlating 3D molecular structures with pharmacokinetic profiles, including structure-permeation
relationships [46], renal clearance [47], metabolic stability [48] and volume of distribution [28].
Milleti
et al
. [49] described a method based on GRID descriptors of molecular interaction fields to predict the pKa
of organic compounds. The pKa is a physical-chemical parameter closely related to lipophilicity and solubility, two
of the most important properties used in pharmaceutical research to study absorption and distribution. The procedure
is based on 4 steps: (1) building of a database of fragments to compute energy minima using the GRID force field;
(2) Describing every atom of the molecule using the MIFs obtained from the database fragments; (3) Describing the
molecular structure around each ionizable site by using binned MIFs summed at each topological distance; (4)
building tables with statistical data containing molecular descriptors and experimental pKa values for different
classes of ionizable sites.
CONCLUSION
The concept and theory of MIFs can be applied as appropriate tools of great importance in the discovery and
development of drugs. These tools have extensive applications and contributions towards determining the energetic
conditions involved in the binding between a ligand and its target via the molecular interaction of a molecule with a
chemical probe. These tools can be used to improve the design of new ligands with enhanced biological activity
based on interaction fields. This strategy can be used in biomacromolecules in order to indentify favorable
interaction regions yielding new proposals for chemical entities which can fit properly in the binding site. MIFs can
also be used with known ligands in order to determine molecular descriptors related with interaction and,
consequently, with biological activity based on the pharmacophore concept. Once inhibitors of a particular
molecular target are available, the derived pharmacophore can be useful in building QSAR models or in screening
virtual databases of drug-like molecules in order to search for potential inhibitors with desired pharmacophore
properties. Nowadays, the MIFs are not only used to find inhibitors but have been extensively used to predict
pharmacokinetic properties of promising drug candidates and help in the proposal of compounds with suitable
pharmacokinetics. One of the major problems in drug candidates failures is due to poor pharmacokinetics and
toxicity. Taking into consideration that the pharmacokinetic profile and toxicity of drugs is governed by molecular
interactions in the human body some descriptors computed by MIFs studies are able to provide information in this
respect and help researchers propose more effective drugs, reducing financial costs.
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