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Medicinal chemistry
Chapter 13 New Methods and
Techniques
Prodrug
• The term prodrug, which was used initially by
Albert HI, is a pharmacologically inactive
compound that is converted into an active drug
by a metabolic biotransformation.
• A prodrug also can be activated by a
nonenzymatic process such as hydrolysis, but in
this case the compounds generally are
inherently unstable and may cause stability
problems.
• The prodrug to drug conversion can occur
before absorption, during absorption, after
absorption, or at a specific site in the body.
• In the ideal case a prodrug is converted to the
drug as soon as the desired goal for designing
the prodrug has been achieved.
Soft Drug
• Soft drugs are biologically active drugs
designed to have a predictable and controllable
metabolism to nontoxic and inactive products
after they have achieved their desired
pharmacological effect.
• The molecule could be deactivated and
detoxified shortly after it has exerted its
biological effect, the therapeutic index could be
increased, providing a safer drug.
Feature
• It has a close structural similarity to the lead;
• It has a metabolically sensitive moiety built into
the lead structure;
• The incorporated metabolically sensitive spot
does not affect the overall physicochemical or
steric properties of the lead compound;
Advantages
• Elimination of toxic metabolites, thereby
increasing the therapeutic index of the drug;
• Avoidance
of
pharmacologically
active
metabolites that can lead to long-term effects;
• Elimination of drug interactions resulting from
metabolite inhibition of enzymes;
• Simplification of pharmacokinetic
caused by multiple active species.
problems
The difference between prodrugs
and soft durgs
• The concepts of prodrugs and soft drugs are
opposite, as follow:
• A prodrugs is an inactive compound that requires
a metabolic conversion to the active form;
• A soft drug is pharmacologically active and uses
metabolism as a means of promoting excretion.
• However, it is possible to design a pro-soft drug,
a modified soft drug that requires metabolic
activation for conversion to the active soft drug.
Hard Drugs
• Hard drugs are nonmetabolizable compounds,
characterized either by high lipid solubility and
accumulation in adipose tissues and organelles or
high water solubility.
• They are poor substrates for the metabolizing
enzymes; the potentially metabolically sensitive
parts of these drugs are either sterically hindered
or the hydrogen atoms are substituted with
halogens to block oxidation.
QSAR
• Quantitative
structure-activity
relationships
(QSAR) represent an attempt to correlate
structural or property descriptors of compounds
with activities.
• These physicochemical descriptors, which include
parameters to account for hydrophobicity,
topology, electronic properties, and steric effects,
are determined empirically or, more recently, by
computational methods.
• Activities used in QSAR include chemical
measurements and biological assays.
• QSAR currently are being applied in many
disciplines, with many pertaining to drug design
and environmental risk assessment.
Molecular Modeling
• A technique for the investigation of molecular
structures and properties using computational
chemistry and graphical visualization techniques
in order to provide a plausible three-dimensional
representation under a given set of
circumstances.
• Computer simulation of molecular structure, to
predict and display shape, calculate minimum
energy conformations and dynamic ranges,
predict recognition sites, binding orientations,
etc.
Rational Drug Design
• Using structural information about drug targets
or their natural ligands as a basis for the design
of effective drugs.
• Rational drug design is a more focussed
approach, which uses information about the
structure of a drug receptor or one of its natural
ligands to identify or create candidate drugs.
• The three-dimensional structure of a protein can
be determined using methods such as X-ray
crystallography or nuclear magnetic resonance
spectroscopy.
Combinatorial Chemistry
• Combinatorial chemistry is a technology for
creating molecules en masse and testing them
rapidly for desirable properties-continues to
branch out rapidly.
• Compared with conventional one-molecule-ata-time discovery strategies, many researchers
see combinatorial chemistry as a better way to
discover new drugs, catalysts, and materials.
High-throughput screens (HTS)
• HTS is very rapid and sensitive in vitro screens
initially developed about 1989-1991.
• HTS now can be carried out robotically on small
(submicrogram)
amounts
of
compound
(dissolved in submicroliter volumes) are
becoming universally used.
• With these ultra-high-throughput screening
approaches, it is possible to screen 100,000
compounds in a day!
Random Screening
• In the absence of known drugs and other
compounds with desired activity, a random
screen is a valuable approach.
• Random
screening
involves
no
intellectualization; all compounds are tested in
the bioassay without regard to their structures.
• Prior to 1935 (the discovery of sulfa drugs), this
method was essentially the only approach;
• Today this method is still an important approach
to discover drugs or leads, particularly because
it is now possible to screen such huge numbers
of compounds rapidly with HTSs.
Nonrandom Screening
• Nonrandom screening, also called targeted or
focused screening, is a more narrow approach
than is random screening.
• In this case, compounds having a vague
resemblance to weakly active compounds
uncovered in a random screen, or compounds
containing different functional groups than leads,
may be tested selectively.
Human genome
• The human genome is made up of all of the DNA
in our chromosomes as well as that in our
mitochondria.
• Our genome also includes every gene we own
plus all of our junk DNA.
• The human genome is both "the treasury of
human inheritance" and a vast dump (or
recycling center).
• Human genome is made up of 23 chromosome
pairs with a total of 3×109 base pairs. There are
about 30,000 genes in human DNA. This was only
twice as many as much simpler organisms.
• However, human genes can make more proteins
than simpler organisms by alternative splicing.
Therefore, the human proteome is about ten
times larger than those of the aforementioned
organisms.
• A working draft of the human genome sequence
was completed in 2000.
• Over the next three years this draft sequence
was converted into a "finished sequence." The
finished sequence covered about 99 percent of
the human genome's gene-containing regions.
• It had been sequenced to an accuracy of 99.99%
by April 2003.
• This feat was achieved by the International
Human Genome Sequencing Consortium which
included hundreds of scientists at 20 sequencing
centers in China, France, Germany, Great Britain,
Japan and the United States.
Genomics
• Genomics is the investigations of an organism’s
genome (all of the organism’s genes).
Protein engineering
• Protein engineering is the application of science,
mathematics and economics to the process of
developing useful or valuable proteins.
• Protein engineering is accomplished by changing
or interchanging individual amino acids in a
normal protein.
• This may be done via chemical synthesis or
recombinant DNA technology.
Proteomics
• Proteomics is the investigations of proteins in the
organism’s proteome to determine their structure
and/or function often by comparison with known
proteins.
• This has become increasingly important
approaches to identify new drug targets.
Chemoinformatics
• The definition according to Dr. Brown (in 1998) is The use
of information technology and management has become
a critical part of the drug discovery process.
• Chemoinformatics is the mixing of those information
resources to transform data into information and
information into knowledge for the intended purpose of
making better decisions faster in the area of drug lead
identification and organization.
• In fact, Chemoinformatics is a generic term that
encompasses the design, creation, organization,
management, retrieval, analysis, dissemination,
visualization and use of chemical information.
Bioinformatics
• Bioinformatics
derives
knowledge
from
computer analysis of biological data. These can
consist of the information stored in the genetic
code, but also experimental results from various
sources, patient statistics, and scientific
literature.
• Research in bioinformatics includes method
development for storage, retrieval, and analysis
of the data.
• Bioinformatics is a rapidly developing branch of
biology and is highly interdisciplinary, using
techniques and concepts from informatics,
statistics, mathematics, chemistry, biochemistry,
physics, and linguistics.
• It has many practical applications in different
areas of biology and medicine.