The revolution of medicinal chemistry had occurred recently. A much better understanding of how the body works- including every organ in the body- at a cellular and the molecular level occurred as a result of the rapid advance in the biological sciences.
In any drug design, there are two major considerations that must be considered:
- The interaction of drugs with molecular targets in the body and the importance of choosing the correct target for the desired pharmaceutical effect. Pharmacodynamics plays an important role in drugs interactions with specific targets, as it is the case of designing that will interact as strongly and selectively as possible with the specific targets.
- Pharmacokinetics is the second major consideration, as it indicates the journey of drugs reaching their specific targets in the body, which indicates the importance of designing a drug that will carry out that journey.
The definition of drugs is defined as compounds that interact with a biological system to bring about a biological response. Drugs fall into two categories, bad and good drugs. The categorisation of drugs depends on the definition and prescription of drugs. “If a drug is to be really ‘good’ it would have to satisfy the following criteria” (Madsen U, Krogsgaard-Larsen P, Liljefors T 2002). ‘good drugs ‘are said to be compounds that fulfil their purpose in the body, don’t contain unwanted or toxic side effects as well being easy to be used. There are no such drugs that accomplish these criteria (Madsen U, Krogsgaard-Larsen P, Liljefors T 2002) as sometimes ‘good drugs’ can be harmful to the body since the concentration of a drug is significantly important in terms of toxicity of drugs, as well as the timing and methods of using a particular drug. For example, high dose of Paracetamol causes liver damage in the human body, which indicates the importance of these factors. An example of a ‘bad drug’ is Morphine. It works as an excellent analgesic, but it also has some serious side effects such as addiction, respiratory depression and tolerance.
Drug discovery is the process of making new medications (drugs) to be used in the market. Previously, drugs were found by recognising the active component from traditional cures or by unplanned, fortunate detection. Later classical pharmacology played an important role in identifying substances that have a desirable therapeutic effect where extracts, artificial little-molecules or products-made-naturally were tested in whole organisms or entire cells as part of the classical pharmacology process. Sequencing of the human genome has become a common method to use high throughput screening of compounds libraries against isolated biological targets, due to its ability to synthesise and clone a huge amounts of proteins in a very short time, these screens are used as disease modifying in an operation called revere-pharmacology. Hits formed from these screens are then tried in animals and cells for effectiveness.
Drug design (rational drug design) is the innovative method of discovering new medications supported by the understanding of a biological target. The designed drugs are usually organic little molecules that suppress or trigger the role of biological molecule such as proteins, which causes a therapeutic benefit to the patient. Basically, drug design involves designing drugs that can bind to their bimolecular targets which are complementary in form and charge to the drugs. This allows drugs to interact and bind to their targets and therefore result in a bimolecular response. Frequently but not necessarily, computer modelling techniques can be an important factor in drug design and it is sometimes referred to as ‘computer-added drug design’. Structure-based drug design is when designing a drug depends on the 3D-structure of a bimolecular target. The stability, affinity and selectivity of Protein-based therapeutics have been developed, by using a class of drugs which includes peptides and especially therapeutic antibodies.
The way of which new a pharmaceutical drug is introduced into the market which is after the recognition of a lead compound in the procedure of dicovering a drugs. It involves pre-clinical and clinical researches.
Pre-clinical research: information about the safety and efficacy of candidate drugs before testing them on humans is on the most important aims of preclinical researches. They also include in-vitro and in-vivo as well as providing us with the evidences for the compound’s biological effects. To ensure reliable results, pre-clinical researches must follow the lows and guidelines determined by the Good Laboratory Practice (GLP), which are required by authorities such as FDA. Deep understanding of the compound’s quantity and toxicity levels are very important to detect whether it is reasonably safe and justified to start the clinical studies. These are provided by researches on toxicology, pharmacokinetics and pharmacodynamics. The knowledge of the physiological and biochemical effects and the way drugs bind to their targets as well as the correlation between the amount of a drug in the body and its response (biological effect) are included in the study of pharmacodynamics (Drews, J., 2000).
Pharmacokinetics is the study of the metabolism, disruption, absorption and excretion of drugs in the body. Preclinical studies are done to determine if a drug is safe to be tested in humans also to find out the treatment method associated with the least degree possible of toxicity, which makes a safe dose to start clinical trials. Pre-clinical researches can used to establish bio-markers for monitoring potential AEs (Bengel, Sherif, Saraste, and Schwaiger, 2010).
Clinical researches: they are researches in which samples of tissue are studied to understand the health and disease. New and better ways to detect, treat, prevent and diagnose diseases can be detected using clinical researches. Clinical trial is a type of clinical researches and it is a way of testing new treatments for a disease to collect health details and understand how a disease progresses and develops over time. The studies or trials performed of people is called clinical research (U.S. Food and Drug Administration, 2018). There are several stages or phases in clinical trials: 1) Phase I trials, which are done to determine dosing and safety and usually done with healthy people. 2) Phase II trial are done in small number of patients having the disease targeted by New Chemical Entities (NCE) to obtain an initial reading and review safety more. 3) Phase III trials are huge trials performed to detect safety and effectiveness in big group of patients with the targeted disease. Clinical testing might stop, if efficacy and safety are sufficiently proved, and the NCE OR NME progress to the new drug application (NDA) phase. 4) Phase IV trials, named as post-market surveillance studies, are post approval trials that are attached by the FDA (Drews, J., 2000).
A number of chemicals (known as neurotransmitters) used to diffuse signals between cells. Acetylcholine is one of the most plentiful neurotransmitters in the body, usually called Ach. Ach occurs in both the peripheral nervous system (PNS) and the central nervous system (CNS). Ach is named after its shape, as It’s made of acetic acid and choline. Ach was the very first neurotransmitter to be identified as well as being the most common chemical messenger in the body. In 1914, Acetylcholine was discovered by Henry Hallett Dale. Later, the confirmation of the presence of Acetylcholine was done by Otto Loewi. In 1936, both scientists were awarded Nobel prizes for the discovery of Acetylcholine (cherry, 2018).
This neurotransmitter, in PNS, is a leading molecule in the autonomic nervous system which functions by activating the muscles. it also manages some roles by affecting pre-ganglionic neurones on both parasympathetic and sympathetic systems. The transmission of signals from motor neurones to the body’s skeletal muscle is on the main roles of Ach (cherry, 2018), where it allows motor neurons to activate muscle actions by acting at neuromuscular junctions in the PNS (Sims, Smith, Davison, Bowen, Flack, Snowden and Neary, 2003).
Acetylcholine (In CNS) acts upon various sites, such as in the brain. Acetylcholine acts as a neuromodulator by affecting a variety of neurones throughout the nervous system, rather than getting involved in a direct synaptic transmission between particular neurons. It also acts as region of a neurotransmitter system, within the CNS, and has a function related arousal and attention (cherry, 2018).
Acetylcholine can bind to two types of Acetylcholine receptors (AChR), in order to carries its signal, which are nicotinic Acetylcholine receptors and muscarinic Acetylcholine receptors. The names of these receptors come from the agonist’s nicotine and muscarine, respectively. The functions of both receptors are different from each other, where the nicotinic type being ligand-gated ion channels that intercede an accelerated synaptic communication of the neurotransmitter, while the muscarinic type being G-protein coupled structure (GPCRs) that intercede a slow metabolic response through 2nd courier cascades.
- Muscarinic receptors: one of their characteristics is their ability to interact with muscarine, which is water-soluble toxin derived from Amanita muscaria (a type of mushrooms) that activates the peripheral sympathetic nervous system as a result of attraction to muscarinic AChRs, causing in seizures and death. An addition of intracellular calcium to carry signals inside cells is part of an intracellular secondary messenger system which is used by G-proteins-coupled receptors including muscarinic AChRs located in the CNS. The shape the muscarinic receptor changes once Ach interacts with the AChR resulting in the organisation and activation of an intracellular G-protein, resulting in the transformation of GTP to its active form GDP then split up from the receptor (Sims, Smith, Davison, Bowen, Flack, Snowden and Neary, 2003).
- Nicotinic receptors: their ability to interact with nicotine (found in tobacco) is one of the major characteristics of these receptors. Pores in cell’s plasma membrane are formed by the ligand-gated ion channels (nicotinic receptors), Interceding fast signal transmission at synapses. There are two types of the physiological processes which are either Neuronal-type or muscle-type. Muscle-type nicotinic AChRs are responsible for muscle tone and located at the neuromuscular junctions (Drews, J., 2000)
Whereas neuronal-type nicotinic AChRs are located at synapses between neurones and have cognitive-function, learning and memory arousal, reward and motor-control in CNS. Ach activates nicotinic AChRs through binding to these receptors, where a conformational change occurs in the receptor after 2 molecules of Acetylcholine are bound to them allowing the formation of ion pore. Rapid increase in cellular permeability of calcium and sodium ions, producing a muscular contraction as a result of the excitation and depolarisation of the muscle cell. Acetylcholine deficiency could cause Myasthenia gravis condition. The voluntary muscles of neck, eyes, face and mouth are typically affected by this autoimmune disorder. pyridostigmine (Mestinon) are given to patients to increases the level of Acetylcholine in the body to be able to stimulate receptors (Sims, Smith, Davison, Bowen, Flack, Snowden and Neary, 2003).
- Synthesis and Metabolism of Acetylcholine:The synthesis of acetylcholine occurs in the parasympathetic nerve terminal, the choline is transferred to the cytosol of nerve endings through a high-affinity choline uptake system. Choline is then acetylated by choline acetyltransferase and then stored into storage vesicles (Bengel, Sherif, Saraste, and Schwaiger, 2010). in order for Ach to bind to muscarinic receptor, Ach is distributed into synaptic . Free Ach is then processed by the enzyme acetylcholine esterase. Samples of patients with Alzheimer’s disease were used to test the metabolism and integration of (U-14C) glucose in Ach (Sims, Smith, Davison, Bowen, Flack, Snowden and Neary, 2003).
- The chemical structure of Acetylcholine bound to an Acetylcholine receptor:
The Acetylcholine (Ach) molecule binds to the muscarinic Acetylcholine receptor (mAChRs) forming an ionic bond between the N+ atom and the CO2- molecule of Trp-307 Asp-311. Hydrogen-bonds are formed between the oxygen atoms on the (Ach) molecule and the hydrogen atoms of Asn-617.
The images below show the structure of Acetylcholine bound to a receptor in BioVia Software.
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