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 problems caused by multiple active species.

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-at- a-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 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 3×10 9 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 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.