Chemistry Reference
In-Depth Information
In addition to the relatively modest computational expense, a major boost for the advancement of the method has
been the assurance that it is a formally exact theory [493]. However, in practice, there is need to use approximate xc
potentials which may lead to errors in the computational results. There have been problems such as description of
Rydberg excitations, treatment of extended π systems, absence of double and higher excitations and the 1/R
dependence of charge-transfer (CT) excitation energies. Although there is belief that any problems with the method
are caused by imperfections of xc potentials it may also be necessary to also consider so-called adiabatic
approximations, in which the time dependence enters the xc functional only via the time-dependent (TD) density
functional as well as time-or energy-dependent xc functional beyond the adiabatic approximation [481, 491].
Although the focus during this decade has been to introduce functional for specific usage, the new trend is to
develop all-purpose functionals.
WEAK INTERACTIONS
Hydrogen bonds (HB) are soft interactions whose bond lengths and angles fluctuate according to local environments
and are dependent on the pair of atom groups that forms the extensive donor and acceptor subunits. The major
component of hydrogen-bonding interaction is electrostatic. They are crucial for binding affinity and dictating the
orientation of an inhibitor binding in the receptor and are thus of great importance to drug design. The bond capacity
of HB is essential for bioisostersm. When a moiety of a compound is replaced by a bioisostere, the HB
characteristics of the parent has to be matched with the possibility of improvement of drug properties. The strength
of hydrogen bond acceptors and donors may vary significantly, and as a result, electron-withdrawing or donating
substituents can have opposite effects on the activities of the compounds, via interactions of the inhibitor with the
receptor [171].
Many structure-activity relationships (SAR) can be traced to modifications of the hydrogen-bonding interaction of
the inhibitor with the receptor. Due to the character of being the property of a group of atoms and having
susceptibility to local environments, HB cannot be modeled accurately by a general semiempirical or rule-based
method. There are many exceptions, such as steric factors, to be accommodated by a finite set of rules. The
directional properties are not isotropic and quite important to both computational studies and practical applications
[171].
In three-dimensional structures of biological macromolecular systems such as proteins and nucleic acids, stacking
involving aliphatic chains, aromatic rings or cations/anions have been widely observed and known to contribute to
thermodynamic stabilization. In many theoretical studies the van der Waals (vdW) energy has been shown to be the
primary origin of the stabilization energy for stacking between aromatic rings. In order to evaluate the electron
correlation effects more sophisticated ab initio calculations are required such as coupled cluster methods with
singles, doubles, perturbation, (CCSD(t) as well as quantum Monte Carlo (QMC) methods. Conventional Hartree-
Fock (HF) and traditional density functional theory (DFT) face difficulties estimating the stabilization energy gained
by stacking aromatic rings. Good consistency can be obtained with CCSD(t) and some DFT methods such as SAPT.
Notwithstanding, the computational cost of using sophisticated approaches for the wdW energy are too large. At the
other end, the usage of empirical functions in molecular mechanics (MM) calculations, in order to reduce the
computational cost have reportedly yielded inadequate results [333,469].
When halogen atoms act as electrophiles, there are specific molecular interaction which has been recently
investigated and known as halogen bonding whose characteristics are parallel with those of hydrogen bonding in
terms of strength and directionality [235]. The effective ability of halogen atoms for directing molecular recognition
processes became more noticeable in the 1990s, and as a consequence in the last decade, this type of bonding has
yielded many applications. Halogen bonding can be important in areas where the control of intermolecular
recognition and self-assembly processes plays a central role. There are important implications of halogen bonding,
or halogen to oxygen (or nitrogen) which are below or equal to the van der Waals radius sums in biological
molecules. The interesting chemical features of halogens make them useful in designing drugs and protein
inhibitors. It is also of interest that about half of the molecules applied in high-throughout screening are halogenated.
The Protein Data Bank contains over 1000 structures in which the ligands are halogenated yielding d(Cl…O),
