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Structure-Based Drug Design

Article · January 2013

DOI: 10.4172/2329-6887.1000e111

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Agrawal, J Pharmacovigilance 2013, 1:4
Pharmacovigilance http://dx.doi.org/10.4172/2329-6887.1000e111

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Structure-Based Drug Design

Prashansa Agrawal*
College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, USA

In today’s world where life is fast-paced, public health is a big with a higher affinity. This method has a plethora of benefits [6] over
concern. With the tremendous ongoing development in the field of the conventional high-throughput screening techniques. For example,
pharmaceutical drugs, people can find cure for a vast variety of diseases. using this approach, one can find more hydrophilic leads whose affinity
These modern-day medicines have been proven to be more effective in can be increased by further addition of hydrophobic groups without
treating, managing, controlling and preventing the diseases and their allowing the overall lead to become too hydrophobic. In addition, these
reoccurrence. For example, cancer patients, who had a very low rate of leads are not expected to contain sterically blocking groups that may
survival in 1970’s, can now be treated more efficiently by chemotherapy. interfere with favorable ligand-protein interaction or higher efficiency.
At present, the cancer death rate has declined by 20% in comparison The application of fragment-based drug design has gained a lot of
to 1990 [1]. However, along with rapid progress in the efficacy of these attention in recent years. It has lead to the discovery of protein kinase
pharmaceutical medicines, have come long-term undesirable side inhibitors [7], matrix metalloproteinase inhibitors [8,9]; site-directed
effects, poor absorption and clearance, multi-drug resistance, excessive ligand discovery for thymidylate synthase [10] and cysteine aspartyl
toxicities, and adverse reactions of these medicines. Hence, there is protease-3 (Caspase-3) [11].
a stringent need to get a closer insight into these drugs in terms of
their structure and function, their molecular interactions with large Structure-based virtual screening
biomolecules (protein, nucleic acids) within the cell, so as to design This is a computational approach which involves rapid searching of
and/or modify the drugs to have improved potency, fewer side effects large libraries of chemical structures in order to identify potential drug
and selective binding to their biomolecular target. candidates (hits) which are most likely to bind to a drug target (protein
Structure-based drug design is a very robust and useful technique. receptors, enzymes) followed by docking of the hit into a protein target
It involves acquisition of the information regarding three-dimensional and application of a scoring function to estimate the probability that
structure of the molecular target (protein) through methods such as the drug candidate will bind to the protein target with high affinity [12].
x-ray crystallography, NMR spectroscopy or homology modeling, The major advantage of this screening is that it improves the hit rate by
followed by design of suitable drug candidates based on the binding considerably decreasing the number of compounds for experimental
affinity and selectivity for their target molecules. With the outburst estimation of their activity and thereby increases the success rate of
of structural and -omics (e.g. proteomics, genomics, metabolomics) in vitro experiments. Structure-based virtual screening has been used
derived data for these protein targets, structure-based drug design consistently in pharmaceutical companies and academic groups for
has become a very potent and imperative tool for discovering lead early-stage drug discovery.
compounds which can be optimized to lead towards the development In silico structure-based lead optimization
of marketable drug products.
After the desired hits are identified through virtual screening, this
The arena of drug design is disseminating very swiftly. The method is used to discover and optimize the lead compound from the
traditional methods, combinatorial chemistry and high-throughput screened hits based on its high affinity for its target and the elucidation
screening (HTS), for screening hits and developing lead compounds of its absorption, distribution, metabolism, excretion and toxicity
have taken a back seat, as they have not been able to effectively (ADMET) properties along with its physicochemical characterization
accomplish the goals of discovering new chemical entities or countering which increases the likelihood for success in clinical phase research.
the ever-increasing research and development costs for these entities This optimization can be reached using various computational
[2]. To overcome these problems, there are now different approaches approaches, which include quantitative structure-activity relationships,
to design drug based on the structural knowledge of the target and the pharmacophores, similarity search, homology models, databases, data
properties of the ligand. mining, network analysis and data analysis tools. However, like every
method, this approach also has its own precincts [13]. The in silico
Structure-Based Drug Design Include
based approach can speed up the search of obtaining the optimized
Fragment-based lead discovery lead by delineating the prediction about its pharmacological properties
and thus reducing the in vitro and in vivo experimental time, but
This method serves to complement the traditional approaches as a sometimes predictions are not accurate due to flexibility of the target,
new paradigm in the generation of lead compounds in the process of
drug discovery. In this procedure, the leads are identified, optimized,
and linked together to produce high-affinity ligands [3] based on the
*Corresponding author: Dr. Prashansa Agrawal, College of Pharmacy, The
structure-activity relationships (SAR), obtained from NMR [4] and University of Arizona, Tucson, Arizona, 85721, USA, Tel: +1 520- 626-6749; E-mail:
various other techniques, between a small chemical fragment and [email protected]
its protein target. The criteria of selecting the chemical fragments
Received June 10, 2013; Accepted June 12, 2013; Published June 14, 2013
is based on the fact that they should be functionally simpler than
drug molecules, have weak potency but efficient binding, have high Citation: Agrawal P (2013) Structure-Based Drug Design. J Pharmacovigilance 1:
e111. doi:10.4172/2329-6887.1000e111
purity and good aqueous solubility, and follow the ‘rule of Three’ [5]
(molecular weight < 300, ClogP < 3, the number of hydrogen bond Copyright: © 2013 Agrawal P. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
donors, acceptors and the number of rotatable bonds each should be < use, distribution, and reproduction in any medium, provided the original author and
3). Then these fragments are expanded or combined to produce a lead source are credited.

J Pharmacovigilance
ISSN: 2329-6887 JP, an open access journal Volume 1 • Issue 4 • 1000e111
Citation: Agrawal P (2013) Structure-Based Drug Design. J Pharmacovigilance 1: e111. doi:10.4172/2329-6887.1000e111

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conformational flexibility and non-selectivity of the lead. In such a case, improving the success rate of drug lead optimization, endowing with
the fragment-based lead discovery strategy can be applied. Hence, all assistance in monitoring safety and assessing the balance between
the approaches are complementary to each other. the hazards and benefits of these drugs either while they are in the
development pipeline or have been approved for marketing, reducing the
ADMET modeling high attrition rates in the clinical phase of the drug development process
ADMET stands for absorption, distribution, metabolism, and decreasing the mortality ratio. In consequence, the structure-based
excretion and toxicology of drugs. This method is also referred to drug design plays a vital role in the field of pharmacovigilance by being
as physiologically-based pharmacokinetic modeling. It is used in complementary to each other in the development of drug discovery.
pharmaceutical research and development, and in health threat
evaluation to predict the ADMET of a compound in humans. There References
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