Computational Molecular Biology 2016, Vol.6, No.1, 1-20
13
site pocket(Cheng et al., 2012). Quantitative structure activity relationship (QSAR) calculates the relative binding
energies of the ligand for studying the interaction of ligands with target (Verma et al., 2010). A steady
conformation of the drug and the protein complex could be derived by applying molecular dynamic simulations
(MD). MD will provide a structure free from structural restraints by the application of appropriate force-field.
This is will further narrow down the screening process (Kerrigan, 2013).
3)
Selection of a clinical candidate: Before
in vivo
studies a lead drug is tested for its pharmacological
properties. In pharmacology and pharmacokinetics four properties of a potential drug absorption, distribution,
metabolism, excretion and toxicity (ADMET) are considered before promoting it to the next level. There are many
commercial softwares (ADMET predictor, MedChem studio, ADMET modeller) as well as web-servers
(ALOGPS, ToxPredict, ADME-Tox) available which can successfully predict these properties of a compound
( Cao et al., 2012).
Clinical Trials : Finally, the selected lead compounds are clinically tested in various animal models and finally on
humans.
5 Conclusion
The NFkB pathway marshals numerous signaling cascades in the cell. These signaling pathways encounter
each-other and develop a complex signaling network in which molecules interact and influence each other’s
functioning. Biochemical assays have provided us with enormous knowledge of these pathways, yet there are
some answers still unknown. Computational modeling which relies on the previous and existing biochemical
evidences and use sophisticated mathematical calculations and theories to join the missing links in the hypothesis.
It provides the clue of which functions related to the object are essential and are to be considered and which one
should be abstracted. Hence, it helps to narrow down the search. As, NFkB mal-function gives rise to chronic
inflammation which lays the foundation for diseases like neuro-degeneration, arthritis, diabetes and cancers,
detailed study of its network and the molecules involved could provide a better understanding of the problem.
Biochemical studies combined with computational modeling can open doors to many questions.
NFkB could be regulated at many levels of the pathway. Apart from others targeting the E3 ligases in the UPS
pathway for drug designing and discovery would provide with drug specificity and less c yto-toxic response.
Unlike other members of the pathway, E3 is responsible for substrate specificity. Mutations or dys-regualtion in
the E3 ligases results in a myriad of chronic diseases. There are drugs available which bind to the HECT and
RING domains of the E3 ligases to abolish their function. But, as there are around 600 E3s, the search is still on.
Computer aided drug designing has open gates to search and screen for molecules which can act as a potential
drug against a target molecule. Use of computational tools like virtual screening, molecular docking and
molecular dynamic simulations act as predictive tools for candidate drug in pharmacology. It narrows down the
search for further clinical trials. Hence, by combining
in vitro, in vivo
and
in silico
approaches the results are more
reliable and with a high success rate.
Acknowledgements
The authors acknowledge University of Kalyani, Kalyani (W.B.) India to provide financial support and
Bioinformatics infrastructure facility (BIF) funded by DBT, India for infrastucture facilities
.
References
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