Protein crystallography has become a mainstream analytical method in assisting the pharmaceutical chemistry field. Specific work on proteases which are instrumental in lead compound discovery have blossomed over the passed two decades as the need for Co-crystallization of target proteins with small molecules is seeing a drastic increase now that their uses in drug design have become fully apparent. Work on phosphorous cleaving and donating enzymes (Kinases and phosphatases) has also become an area of current interest as potential cancer therapy by affecting the energy yield in a cancer cell through interruption of ATP generation. “The use of protein crystallography is highly influential in structure-guided drug design as researchers can help determine the absolute stereochemistry of a compound and alter it if necessary to favour the necessary binding conformation”3.
Co-crystals:
Pharmaceutical Relevance:
Co-crystals have come up in pharmaceutical chemistry as an important and controversial topic. Although there is disagreement on the definition of what is classified as a co-crystal, their importance in pharmaceutical chemistry and X-ray crystallography is noted. Co-crystals are believed to be a crystalline structure of at least two components composed of atoms, molecules or ions. These components form a single unique crystalline structure and have proven to be quite beneficial in vitro as a medicinal delivery system.
Pharmaceutical Advancement:
Several advances on the design, growth and characterization of co-crystals have increased exponentially over the past several decades. It has only been in the past several years however, that reference to pharmaceutical chemistry has begun to flourish as the discovery that ...
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...ghout all stages of the discovery process. “One such computational approach that can go hand-in-hand with major phases of drug discovery such as “hit identification” and “hit-to-lead”; the initial phase involves the identification of a list of chemical compounds, known as ‘hits’, that ideally exhibit some degree of potency and specificity against the target. Whereas, the latter engages evaluation of the screened hits to identify the promising lead molecules before proceeding toward a large-scale lead optimization”7. With drug design rapidly turning into a science of discovery time reduction and results a conglomerate of different methods are being pooled together to assist in “hit identification”. The use of bioinformaticians, systems biologists, and computational clustering methods has allowed researchers validate desired biological targets at a lightning pace.
The IR spectrum that was obtained of the white crystals showed several functional groups present in the molecule. The spectrum shows weak sharp peak at 2865 to 2964 cm-1, which is often associated with C-H, sp3 hybridised, stretching in the molecule, peaks in this region often represent a methyl group or CH2 groups. There are also peaks at 1369 cm-1, which is associated with CH3 stretching. There is also C=O stretching at 1767 cm-1, which is a strong peak due to the large dipole created via the large difference in electronegativity of the carbon and the oxygen atom. An anhydride C-O resonates between 1000 and 1300 cm-1 it is a at least two bands. The peak is present in the 13C NMR at 1269 and 1299 cm-1 it is of medium intensity.
Rogers, D. H.; Morris, J. C.; Roden, F. S.; Frey, B.; King, G. R.; Russkamp, F. W.; Bell, R. A.; Mander, L. N. Pure Appl. Chem., 1996, 68, 515.
David and John Free. (26 Nov 2006). MadSci Network: Chemistry. Retrieved on March 6, 2011, from http://www.madsci.org/posts/archives/2007-02/1171045656.Ch.r.html
...le of the specific binding to metal molecular cations. 18-crown-6 and 15- crown ethers are used for the recrystallization of AN from non aqueous solvents. The crystals formed by this method showed decrease in hygroscopicity . T. Lee et al. used crown ethers to minimize the polymorphic transition near room temperature. The room temperature phase transition is minimized by forming 1:1 co-crystal of AN-benzo-18-crown-6 with a melting point of 125-129 0C. One disadvantage of this Phase stabilized AN is that it reduces the burn rate of the propellant. Organic compounds, those are having crystallographic structure close to AN crystalline structure are also used as phase stabilizers. N. Galavina et al. have been studied the phase stabilization of AN using the organic compounds containing plane unsaturated N-Heterocycles substituted by carbonyl, amine or imine groups.
Svec and Frechet (1992) developed continuous methacrylate rods from glycidyl methacrylate (GMA) and ethylene dimethacrylate (EDMA) as monomer and crosslinker. These two discoveries had a great impact, as they prov...
Methyl benzoate (0.20 ml), Sulfuric acid (0.45 mL of 18 M), and a spin vane was added to a 5 mL conical vial. An air condenser is attached and clamped to allow proper stirring. A second ice bath was made to hold a 3-ml conical vial of Sulfuric acid (0.15 ml of 18M), and Nitric acid (0.15 ml of 16M). This was added dropwise at two and half minutes per drop to the 5 mL conical vial. This was done slowly so as not to produce TNT. Once completed, the 5 mL vial containing the solution was allowed to warm up to room temperature and sat for 15 minutes undisturbed. Two grams of ice was placed in a 30 mL beaker in which the solution was poured over it. The solution was rinsed with cold water and suction filtered when the ice was melted. The crystals were washed with cold water (2 - 1.0 mL), and methanol (0.3 mL). The product was recrystallized using methanol and allowed to dry. The final beige crystals were weighed, and tested for quality.
Sequence and structural proteomics involve the large scale analysis of protein structure. Comparison among the sequence and structure of the protein enable the identification on the function of newly discovered genes (Proteoconsult, n.d.). It consists of two parallel goals which one of the goals is to determine three-dimensional structures of proteins. Determine the structure of the protein help to modeled many other structures by using computational techniques (Christendat et al., 2000). This approach is useful in phylogenetic distribution of folds and structural features of proteins (Christendat et al., 2000). Nuclear magnetic resonance (NMR) spectroscopy is one of the techniques that provide experimental data for those initiatives. It is best applied to proteins which are smaller than 250 amino acids (Yee et al., 2001). Although it is limited by size constraints and also lengthy data collection and analysis time, it is still recommended as it can deliver strong results. There are two types of NMR which are one-dimensional NMR and two-dimensional NMR. One-dimensional NMR provides enough information for assessing the folding properties of proteins (Rehm, Huber & Holak, 2002). It also helps to identify a mixture of folded and unfolded protein by observing both signal dispersion and prominent peak. Observation in one-dimensional spectrum also obtains information on molecular weight and aggregation of molecule under investigation. In spite of this, two-dimensional NMR are used for screening that reveal structural include binding, properties of proteins. It also provides important information for optimizing conditions for protein constructs that are amenable to structural studies (Rehm et al., 2002). NMR is a powerful tool which it w...
Various methods such as x-ray crystallography, NMR, and site-directed mutagenesis are applied to study how AP structure contributes to its function and how cofactors and amino acid residues affect reaction mechanism. Enzymes that retain similar structure and function to E. coli AP are found in other species and organisms. For instance, the physiological functions of human AP are still not known at present, but the level of alkaline phosphatase in bloodstream can be a valuable indicator to diagnose liver and bone diseases. Also, mutation in structural gene of human AP will result in hypophosphatasia, a metabolic disease that interfere with uptake of phosphorus and calcium. Thus, understanding the functions of metal ions and reaction mechanism of E. coli AP will provide a general insight of how other enzymes work and discover future potential use of AP in different areas of research or clinical
In the last 30 years, data obtained from spectrometric measurements, Xray and electron diffraction studies, and other experiments have yielded precise information about bond distances, angles, and energies. In many cases, the data confirmed conclusions reached earlier. In other cases, valuable new insights were acquired. Structure theory has advanced far beyond the simple electron dot representations and now rests securely on the foundations of quantum and wave mechanics. Although problems involving only simple molecules can now be solved with mathematical rigor, approximations such as the valence bond theory and the molecular orbital theory are very successful in giving results that agree with experimental measurements.
To form an ice crystal you need a structure that can be repeated periodically (ESRF). This is not possible with five-fold coordinated groups. In a ...
During this time I learned how to use the computational chemistry programs Spartan and AutoDock Vina in order to perform a similarity analysis on anti-epileptic drugs. The goal of this project was to determine which drug has the best fit based on the calculated binding affinity to the active site on the GABA-A receptor in the human brain. This research is important because it provides useful information to Medicinal Chemists
During the past two decades significant research effort has been made to develop a better understanding of the crystallization mechanisms like nucleation, growth etc, as well as on the modeling and control of crystallization systems. The advancement in process analytical technology and computing power has made this task much easier. The key developments have occurred in novel crystallization concepts, modeling, monitoring and control. A major development in the modeling area is the use of multi-dimensional population balance models which gives the morphological model of crystallization processes, as well as in the better understanding of crystallization in impure media. Developments in...
Heterocyclic compounds are of particular importance as they are associated with a wide variety of physiological activities. A good number of synthetic and naturally occurring heterocyclic systems find use in medicine, dyes, pesticides, agrochemicals, polymers etc. Heterocyclic systems are important building-blocks for new materials possessing interesting electronic, mechanical or biological properties and a number of its derivatives have been marked as valuable commercial products.
Ionic compounds, when in the solid state, can be described as ionic lattices whose shapes are dictated by the need to place oppositely charged ions close to each other and similarly charged ions as far apart as possible. Though there is some structural diversity in ionic compounds, covalent compounds present us with a world of structural possibilities. From simple linear molecules like H2 to complex chains of atoms like butane (CH3CH2CH2CH3), covalent molecules can take on many shapes. To help decide which shape a polyatomic molecule might prefer we will use Valence Shell Electron Pair Repulsion theory (VSEPR). VSEPR states that electrons like to stay as far away from one another as possible to provide the lowest energy (i.e. most stable) structure for any bonding arrangement. In this way, VSEPR is a powerful tool for predicting the geometries of covalent molecules.
... of a protein-enzyme system in order to regulate that metabolic pathway. The only way a drug can mimic a human protein receptor and change its conformation is through the concept of an isomer. The drug will have the same atom kind and number, leading to an identical chemical formula. However, the function will vary, making the drug effective in the metabolic pathway. These examples are enough to prove that the understanding of the concept of isomerism is essential to life. Without understanding isomerism, it is nearly impossible to explain the millions of variations in organic molecules, which are the major components of life. Even though there is currently extensive information of the classification of isomers, research is still underway. Just like any other concept of chemistry, new discoveries are yet to be made that are yet not understood or remain in the dark.