Chemistry Reference
In-Depth Information
structures deposited in the PDB (validation tool and resolution structures). In
addition to ligand coordinates, it may also be necessary to use experimental data
(R-factor) for docking validation. In addition, it may be of interest to consider an
ensemble of structures (different tautomeric, protonation states, stereochemistry,
conformations) [821].
Regarding benchmark bias in decoys we note the following. The sets can have
limitations due to restricted physicochemical similarity, small synthetic feasibility
and restricted number of decoys. On the road for improvements it may be
necessary to use on-the-fly generation of decoys, multiple decoy sets, increase
feasibility for any active and matching properties between actives and inactives as
well as virtual decoy sets. For time and resource efficient target-dependent
evaluation of docking programs, the creation of tailor-made decoy sets for given
sets of actives and inactives may be important.
The usage of high performance, grid and cloud computing, previously discussed is
another route for improving docking and virtual screening outcomes. The usage of
these protocols are indicating increasing scale-ups and speed-ups of both
individual dockings and virtual screens.
SELECTED APPLICATIONS OF VARIOUS MODELS TO DRUG
DESIGN
During the last decade, we have applied many of the methods discussed in this
chapter to Cancer, Aids, Diabetes, Alzheimer, Parkinson and other diseases.
In 2002 we made a theoretical
ab initio
study of ranitidine We used the HF and
MP2 methods in order to investigate the open and folded ranitidine conformations
and found good agreement with experimental crystallographic data. Our results
suggested that, as in metiamide, the folded conformation is also preferred. We
investigated electrostatic, hydrogen bond, solvent effects and charge distributions
on stabilizing the conformations. The interactions of ranitidine with the biological
receptor was discussed [1].
In 2003 we investigated nucleoside analogs that inhibit human immunodeficiency
syndrome (HIV-1) reverse transcriptase such as AZT, d4T, ddI, 3TC and ddC
