Journal of Analytical & Bioanalytical Techniques
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The Exploration of privileged structures in drug discovery is a rapid emerging
theme in Medicinal Chemistry. Privileged structures/substructures, is a single
molecule frame work able to provide ligands for diverse receptors. Privileged
structures represented as ideal source of lead compounds. These structures must
display key physicochemical characteristics that facilitate their ability to bind with
multiple receptors. The main objective was to design inhibitors for Dihydrofolate
Reductase (DHFR) and Thymidylate Synthase (TS) enzymes. The blocking of the
enzymatic activity is a key element in the treatment of many diseases including
cancer, bacterial, protozoal and also opportunistic infections associated with AIDS
like Pneumonia and Toxoplasmosis. Our computationally designed privileged
structures having characteristic requirements like low Molecular weight, cyclic
structure in scaffolds, since they provide molecular rigidity, allowing less entropy
to be lost upon binding to the receptors and also providing better bioavailability.
In addition to the above characteristics of privileged structures medicinal chemist
favorite suite of descriptors like rotatable bonds, polar surface area and Lipinski�s
drug like characteristics have been applied. The designed molecules along with
existing ligands with known activity, when docked into the multiple receptors of DHFR
(1OHJ, 1MVS, 1S3V, 1KMS, 1KMV, 1DHF, 1MVT, 3GHC and 3GHW) extracted
from protein data bank have shown greater binding affinity with these receptors. In
order to further evaluate these results homology modeling of bovine and rat liver
DHFR were established based on the template structures of mouse DHFR (PDB
entry 1FZJ and 3D80) respectively using MODELLER 8v2 program. These results
were assessed as reliable structures by PROCHECK, Verify 3D and PROSA 2003.
These structurally diverse ligands were docked into the active site of modeled
3D structures of rat liver, bovine and also into the template structure of mouse
DHFR using Glide 4.0 to identify important protein ligand interactions. Interestingly
all these molecules showed greater affinity towards the active site showing 7-9
hydrogen bond interactions. When docked into the active site of pneumocystis
carnii (1DYR) and modeled bifunctional protein Toxoplasma gondii (Tg) having 610
amino acids. Tg model was generated taking the modeled TS having 290 amino
acids that was build using 1HVY template and DHFR having 248 amino acids was
modeled using 1J3K and 2BL9 as templates. The linker region between these two
proteins consisting of 72 amino acids was modeled using 1ON3 as a template.
This bifunctional protein modeled by this process was very much refined compared
to the conventional modeling scenario. The docking results were impressing by
showing designed molecules to be top ranked compared to the existing molecules.
Several classical and non- classical inhibitors of Thymidylate synthase with wide
range of inhibition constants were taken and QSAR model was generated using
multiple linear regression (MLR) method, this gave a good predictive model with
= 0.959 and r
= 0.871 with leave-one-out method with cross validation r
0.587. All the existing and designed molecules were docked into the TS (Human
and E.coli) active site and existing molecules showed maximum 1-2 hydrogen bond
interactions. The designed molecules had 6-8 hydrogen bonds with the active site.
In the current docking studies on multiple receptors with 75 diverse structures, it is
established that the designed molecules showed better binding affinity in terms of
estimated dock scores. Hence, suggesting that these diversity oriented privileged
molecules can be considered as most potent anti cancer agents.
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