There is a large number of possible fragment combinations. A small perturbation of the previous fragment conformation would cause great difference in activity. In order to find the lowest binding energy on the Potential energy surface (PES) between fragments and a receptor pocket, the scoring function calculation would be performed for every step of conformation change of the fragments derived from every type of possible fragments combination. Since this requires a large amount of computation, using different tricks may use less computing power and let the program work more efficiently. When a ligand is inserted into the pocket site of a receptor, groups on the ligand that bind tightly with the receptor should have the highest priority in finding their lowest-energy conformation. This allows us to put several seeds into the program at the same time and optimize the conformation of those seeds that form significant interactions with the receptor, and then connect those seeds into a continuous ligand in a manner that make the rest of the ligand have the lowest energy. The pre-placed seeds ensure high binding affinity and their optimal conformation determines the manner in which the ligand will be built, thus determining the overall structure of the final ligand. This strategy efficiently reduces the calculation burden for fragment construction. On the other hand, it reduces the possibility of the combination of fragments, which reduces the number of possible ligands that can be derived from the program. The two strategies above are widely used in most structure-based drug design programs. They are described as «Grow» and «Link». The two strategies are always combined in order to make the construction result more reliable.
The idea that the effect of a drug in the human body is mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemicals are required for the biological activity of the drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of crude extracts, became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine, the active agent in opium, and digoxin, a heart stimulant originating from Digitalis lanata. Organic chemistry also led to the synthesis of many of the natural products isolated from biological sources.
Later, small molecules were synthesized to specifically target a known physiological/pathological pathway, rather than adopt the mass screening of banks of stored compounds. This led to great success, such as the work of Gertrude Elion and George H. Hitchings on purine metabolism, the work of James Black on beta blockers and cimetidine, and the discovery of statins by Akira Endo. Another champion of the approach of developing chemical analogues of known active substances was Sir David Jack at Allen and Hanbury’s, later Glaxo, who pioneered the first inhaled selective beta2-adrenergic agonist for asthma, the first inhaled steroid for asthma, ranitidine as a successor to cimetidine, and supported the development of the triptans. Of all these innovators, perhaps the most notable was Gertrude Elion. Working mostly with a group of fewer than 50 people on purine analogues, she contributed to the discovery of the first anti-viral; the first immunosuppressant (azathioprine) that allowed human organ transplantation; the first drug to induce remission of childhood leukaemia; pivotal anti-cancer treatments; an anti-malarial; an anti-bacterial; and a treatment for gout.
Its duration of analgesia is about 3–4 hours when administered via the intravenous, subcutaneous, or intramuscular route and 3–6 hours when given by mouth. Morphine is also used in slow release formulations for opiate substitution therapy (OST) in Austria, Bulgaria, and Slovenia, for addicts who cannot tolerate the side effects of using either methadone or buprenorphine, or for addicts who are «not held» by buprenorphine or methadone. It is used for OST in many parts of Europe although on a limited basis.
In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde and retrograde memory, but these effects are minimal and are transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.
Other electrical effects include an initial brief increase in action potential, followed by a decrease as the K+ conductance increases due to an increased intracellular amounts of Ca2+ ions. The refractory period of the atria and ventricles is decreased, while it increases in the sinoatrial and AV nodes. A less negative resting membrane potential is made, leading to increased irritability. Other, more indirect effects are cholinomimetic because of vagal stimulation, giving rise to AV nodal delay.
Proteins can be informally divided into three main classes, which correlate with typical tertiary structures: globular proteins, fibrous proteins, and membrane proteins. Almost all globular proteins are soluble and many are enzymes. Fibrous proteins are often structural, such as collagen, the major component of connective tissue, or keratin, the protein component of hair and nails. Membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane.