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A steroid sex hormone that is an intermediate in the production of testosterone and estrogen from cholesterol order sildenafil online now, androstenedione has both androgen and estrogen activity order 100 mg sildenafil free shipping. Translation: the other members of the family can’t trigger the androgen sequence of events buy sildenafil 75mg with amex, whether good (building muscle and bone purchase sildenafil australia, boosting confidence and libido) or not good (hair loss, rogue hair growth). What the ancillary androgens offer is the intermediate prehormones needed for production of testosterone and estrogen. Excess Androgens and Insulin Resistance In my practice, I’ve seen many women who got the brushoff from their primary- care doctors when they expressed concern over thinning locks or raging acne. Yet the problems go far beyond losing or gaining hair or having a complexion like your teenage daughter’s. Most women with high androgens suffer from insulin resistance, and androgens and insulin have their own tango. Insulin resistance is when you need higher and higher levels of insulin for the same result —that is, to drive glucose into cells as fuel. It’s the law of diminishing returns: over time, insulin becomes less effective at lowering blood glucose because the cell becomes numb. This combination results in more free testosterone charging around the bloodstream like a bull in a china shop. Here’s the lowdown: insulin is made in the pancreas, and under normal circumstances, its release is finely calibrated to produce just the right amount so that glucose is extracted from food in your gut, sent into your bloodstream, and then driven into cells, particularly the fat, muscle, and liver cells. Once insulin gets glucose inside the cell, the cell can get busy with crucial tasks such as growth, movement, and repair. With insulin resistance, insulin is banging on the door of the cell like an irate neighbor, yet the cell can’t be bothered with opening the door anymore, so the pancreas gets the message to make more insulin. Then a vicious cycle is off and running, and the knock of the insulin just gets louder and louder—insulin levels rise and the cell is numb. Insulin is also a fat- storage hormone, so you deposit more fat, notably at your waist. When you need higher and higher amounts of insulin to deliver glucose as fuel to your cells, you burn out the ability of the pancreas cells (islet cells, to be precise) to keep up with demand. When this happens, you cannot stabilize your blood sugar within the normal range anymore—defined as a fasting blood sugar of less than 87 mg/dL. Your blood sugar rises, initially to prediabetes levels, and possibly to the diabetes range. Insulin Resistance Is a Bad Neighborhood for Your Cells Insulin resistance heralds several serious problems, including excess weight, obesity, prediabetes, diabetes, dementia, Alzheimer’s, stroke, and some cancers. Here’s an analogy: insulin resistance fosters a bad neighborhood around the cells of your body, but instead of drive-by shootings, muggings, and other high crime influencing your vulnerable cells, you have too much sugar, inflammation, clogged arteries, and weight gain. These problems lead to accelerated aging, wayward hormones, and poor organ reserve. It’s the classic chicken or egg scenario: it’s not clear whether high androgens cause insulin resistance or insulin resistance causes high androgens. Either way, we know that high insulin levels drive the ovaries to make more testosterone. Insulin resistance is also a major factor in the troubling condition called metabolic syndrome, a cluster of ominous signs that are linked to a greater risk of diabetes and heart disease; it affects one in four women in the United States. If you answered yes to the question about ovarian cysts, consider having an ultrasound to find out if you have multiple small cysts in a characteristic string-of-pearls pattern, the “Pearl Sign. Indeed, simply having menstrual irregularities or symptoms of high androgens increases your risk of diabetes by 50 percent. Of all of the problems I see in my practice, balancing insulin and glucose is the biggest challenge. This is because of the serious health consequences and the great difficulty most of us have eating less sugar and fewer carbohydrates. It’s a common thread in my practice to see patients who struggle to limit pizza, pasta, and pie. Insulin resistance: • raises the activity of aromatase, the enzyme chiefly responsible for estrogen production, which sets the stage for estrogen dominance and lack of ovulation. While scientists lack consensus on the best way to measure your sensitivity or resistance to insulin, here’s my advice: ask your doctor to measure your levels of glucose and insulin after you’ve fasted for eight to twelve hours (check with your local lab). I believe the optimal range for blood glucose after fasting is 70 to 86 mg/dL; insulin should be less than 7 mcU/mL. Most gynecologists use a glucose- to-insulin ratio to determine if a patient is insulin resistant. Causes of Excess Androgens While they vary according to the specific type of androgen, the main causes for high androgens are genetics, chronic stress, and excess body fat. It’s often easy to blame our parents for everything, but sometimes that blame is appropriate. From looking at how symptoms cluster in families, we know that genetics plays an important role in androgen levels. Some women have high androgens simply because they are habitually stressed and their bodies are rebelling. Continual stress can throw your adrenal glands into overdrive, increasing the release of stress hormones, such as cortisol, and also increasing the level of androgens. They’re the bosses of hormone underlings, estrogen and testosterone, who vary in brains and brawn. If you are trying to conceive, I recommend asking—no, demanding—that your doctor do a blood test to check your fasting insulin, glucose, progesterone on Day 21, and leptin. Before you go the übermedical route, you may be able to improve your fertility with a few small lifestyle and food changes specifically targeted to women who want to get pregnant. Short version: the maturation sequence of the eggs is disturbed so that there is a breakdown and ovulation doesn’t happen. It’s more that the multiple cysts, along the periphery of the ovaries like a string of pearls, are along for the ride—they are a sign that ovulation is not happening. They are not the type of cysts that require surgical removal and, unlike some other cysts, are not associated with an increased risk of ovarian cancer. Symptoms are varied and manifest differently over time, which makes it very difficult to determine a precise, uniform definition of the syndrome. When you have too much androgen circulating in your bloodstream, it can stimulate your hair follicles to thicken and grow. The result can be increased hair growth on the upper lip, chin, breasts, between the breasts, back, belly, arms, and thighs. The risks can last a lifetime: insulin resistance, high ovarian output of androgens, and inflammation all persist after menopause. Over time, this can lead to buildup of the uterine lining and precancerous changes. Classic signs then appear, such as irregular periods, acne, increased hair growth (on the chin and chest), and sometimes acanthosis nigricans, a dark-colored, velvety discoloration on the underarms and back of the neck. Before I tell you why I don’t think you should be in a rush to slime your hair follicles every day or remove every molecule of testosterone in your body, let’s first consider why we’re doing so poorly with hair loss. Sometimes hair loss is associated with high androgens, but more commonly, I find in women that the root cause is low iron, thyroid hormone imbalance, or insulin resistance. Before my patients start looking for a solution to their hair loss in a box from the drugstore or a pill bottle from a dermatologist, I encourage them to look inside their bodies. Remember that most symptoms women try to solve with a pill bottle are a message from the body that something is awry. To find a patient’s particular reason for hair loss, I order the blood panel listed below. Minoxidil, which you can buy without a prescription, is actually a drug for lowering blood pressure, but when applied topically, it slows hair loss and promotes regrowth. It dilates blood vessels, allowing more oxygen, blood, and nutrients to reach the hair follicles, resulting in new, thicker, and better hairs. If you are wigging out because of hair loss and need to do something while investigating root causes, I recommend parting your hair down the middle, snapping a few photos (your smartphone works nicely) to document the width of your part and your hairline, and applying the lower dose to your scalp (2 percent minoxidil, not the higher dose for men, which is 5 percent). Unfortunately, there’s no cure —when you stop using minoxidil, you will return to the rate of hair loss you had unless you’ve corrected the cause. Minoxidil has been used for more than thirty years, so it’s got a longer track record.

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She had intestinal flukes and stages buy 100 mg sildenafil visa, human liver flukes and Trichinella in the brain cheap sildenafil 50 mg with mastercard. She also had propane and asbestos in her brain from leaky pipes and a worn washing machine belt purchase sildenafil visa. They eagerly removed the platform buy sildenafil 50 mg with amex, found the oil on the water surface, cleaned everything up carefully, until no benzene could be found which put her on the road to recovery. Norma Luellen, a young mother, had tingling, numbness and weakness on the entire left side of her body. She had intestinal flukes and their stages, not in the intestine or liver or thymus, but in her brain! In spite of staying on the parasite program she got reinfected with sheep liver fluke, probably from eating hamburgers. She was not able to stop her carbonated beverage habit and frequently showed xylene, acetone, methylene chloride in addition to pentane in her white blood cells. She had intestinal flukes in the brain (cerebrum and cerebellum) but none in the intestine! She also had bismuth (cosmetics), palladium, copper, samarium, and tellurium (tooth alloys) in her brain. She began to improve enough to be off Prednisone by her 10th day of the parasite program. She was on Prednisone but her balance was getting so bad she had to be in a wheelchair. Her brain was full of gasoline; she used to work at a gas station and now was getting it from the attached garage. She had human liver flukes, sheep liver fluke and Trichinellas and dog tapeworm stages in her cerebellum (motor control center). After killing parasites and starting to take thioctic acid (4 a day) and cleaning up her environment she improved enough to drive a car again, walk without a cane in her home. He was full of kerosene and benzene possibly from fuel oil that he pumped for a living. He also had mer- cury and thallium in his immune system which came from tooth fillings. And they were giving him the classical symptoms: numbness of hands and feet and gradual destruction of his nervous system. The fact that one child was beginning to show similar symptoms strengthened their belief in the gene theory. Ten days later his inappropriate laughter stopped; he could get his right hand to his face, he walked twice as fast and had very little tremor remaining. Strong chelating treatments obtained at a Mexican clinic had drawn much of the mercury and thallium out of his brain. He killed the flukes and Shigella bacteria electronically and stopped consuming unboiled milk. The brain solvents, xylene and toluene were removed quickly, too, as well as asbestos. His fast improvement showed them how important it was to remove the source of these pollutants in his home. Two days later he regressed considerably which made him feel quite depressed, since his chelating treatments had not stopped. He had inadvertently eaten a non-sterile dairy food: milk added to soup when it was already done cooking! He zapped the bacteria again and applied greater vigilance to eating only sterilized dairy foods. Then they scheduled their dental work, which had already been done once two years ago! Now, selecting a dentist with experience in finding tattoos and cleaning cavitations made much more sense to him than it had before. And to stay out of the workshop until the asbestos- containing belt had been replaced and the furniture painting had been moved to a different building. High Blood Pressure High blood pressure is one of the easiest problems to correct without resorting to drugs. The most important change to make is to stop using caffeine as in coffee, tea, or carbonated beverages. Switch to hot milk or hot water if a hot beverage is desired, or any of the beverages given in the recipe section. If being without caffeine leaves you fatigued, take an arginine tablet in the morning (500 mg). Blood pressure is mainly controlled by the adrenal glands which sit like little caps on top of the kidneys. You could do your search in the kidneys since kidney tissue is available in grocery stores. Conducting or storing drinking water in containers of metal is as foolish a practice as eating food off the floor. You may not see what it picked up any more than you can see if it has picked up sugar or salt. If you find cadmium in your hot or cold water, you will never be able to filter it out. The amount of cadmium in your clothing from doing laundry with this water is already too much for your adrenals and kidneys. If you believe you already have plastic pipes or all copper (which leads to leu- kemia, schizophrenia and fertility problems) you will need to search every inch of plumbing for a very short piece of galva- nized pipe left in the system! The toxicity of cadmium, in fact, the high blood pressure connection, has been known a long time. All (100%) cases of high blood pressure I have seen could be easily cured by eliminating cadmium and other pollutants, followed by cleansing the kidneys. To test whether you still need your blood pressure medicine, wait until your pressure is down to 140/90 or better. If it has climbed back up you are not ready; go back to ¾ or a full dose of medicine. If your blood pressure stays down, cut your medicine in half again (you are now down to ¼ the regular dose) and see if your blood pressure stays improved. Better yet, make a salt that is a mixture of sodium and potassium chlorides (see Sources). The sodium portion could be sterilized sea salt (test and make sure it has no alumi- num silicate in it first). Rinse these thoroughly first, throw away shriveled ones, and add vitamin C to the cooking water. Bala Cuzmin, age 72, had high blood pressure for ten years but the upper (systolic) pressure remained high in spite of various medi- cines that were tried. She stopped using caffeine, switching to arginine tablets to get over the let-down. Her diet was changed to reduce phosphate and add calcium, and she took magnesium and Vitamin B6 to assist the kidneys. She killed parasites, cleansed kidneys but saw no drop in blood pressure which stayed at 150 to 170 systolic. She had all the metal in her mouth replaced and promptly saw a blood pressure drop to 145-1 50. She had phosphate crystals in her kidneys and was started on kidney herbs and a diet change to include milk and exclude soda pop. She was feeling so much better after the kidney cleanse that she decided to remove her last fillings and replace her bridge, too, since it was shedding ruthenium. On her way home from the dentist, her ears stopped ringing and soon her blood pressure was down to 126/68. She was still on half a dose of drugs because she was too afraid to go off entirely. This gave her the energy she wanted to play basketball with the grandchildren again. Then he could cut back on his medicines, measuring his blood pressure daily to guide him. After seven weeks it was down to 140/85, so he decided to do without medicine, a bit early.

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In clinical studies conducted to determine whether personality psychopathology is common among anabolic steroid users discount 75mg sildenafil fast delivery, illicit androgen users were compared with age-matched alcoholics and two control groups sildenafil 100mg mastercard. Results from these studies showed that androgen users had increased risk for person- ality psychopathology when compared with community controls order sildenafil uk. Furthermore cheap sildenafil 25 mg without a prescription, illicit androgen users also demonstrated significant antisocial traits in a manner similar to the alcoholic group. Table 7A () Table 7B Basic Physical Properties of -Agonists and Other Selected Drugs adrenoceptor agonists for a period of about 1 yr can accelerate a decline in pulmonary function in asthmatics. Additionally, terbutaline produces cardiostimulation, but to a lesser degree than isoproterenol. Treatment with 5 mg terbutaline orally three times/ daily every 6 h (15 mg/d maximum dose). Subsequently, repeat in 15–30 min if needed (4-h delay prior to subsequent treatments). The rate-limiting enzyme in catecholamine synthesis is tyrosine hydroxylase, a cyto- solic enzyme, which catalyzes the formation of L-dopa (3,4-dihydroxy-L-phenylalanine) from the substrates tyrosine and oxygen. Biopterin is the cofactor for tyrosine hydroxy- l-ase and may serve as a regulator controlling the velocity of the reaction. Another func- tion of tyrosine hydroxylase is in production of additional tyrosine through the hydroxyla- tion of phenylalanine. However, phenylalanine hydroxylase is the enzyme primary enzyme responsible for the hydroxylation of phenylalanine. L-dopa is converted into dopamine through the action of the enzyme dopa decarboxylase, a pyridoxine-depen- dent enzyme, which removes the carboxyl group from dopa. Dopa decarboxylase, also referred to as aromatic amino acid decarboxylase, can also act on 5-hydroxytryptophan to form serotonin. Dopa decarboxylase is found in both catecholaminergic and sero- tonergic neurons and nonneuronal tissues (e. Dopamine is then acted on by the enzyme dopamine -hydroxylase that hydroxylates the -car- bon on the ethylamine side chain forming norepinephrine. Both dopamine -hydroxy- lase and tyrosine hydroxylase are mixed function hydroxylase that use molecular oxygen. Also, the highest concentration of dopamine -hydroxylase is found in vesicles that store catecholamines. Further conversion of nor- epinephrine to epinephrine takes place in a few neurons of the brain stem that utilize epinephrine as a neural transmitter and in adrenal medullary cells that secrete epineph- rine as the primary neurohormone. The Following Classes of Drugs May Interact with -Adrenoceptor Agonists 2 and Other Sympathomimetics When Administered Concurrently (25,63) 14. Less frequent effects are asthenia, back pain, bone pain, pelvic pain, arthralgia, dyspnea, hypertension, increased cough, pharyngi- tis, rash (unspecified), vasodilation, and edema. The most frequent adverse reactions are bone pain, back pain, hot flashes, nausea, arthralgia, and dyspnea. The most common adverse effects include hot flashes, fatigue, pain (unspecified), depression, insomnia, anxiety, dyspnea, dizziness, headache, and weight gain. Less frequent adverse effects include arthralgia, alopecia, confusion, dyspep- sia, respiratory infections, and urinary tract infections. Adverse reactions include drowsiness, morbilliform skin rash, nausea/vomiting, anorexia, adrenal insufficiency, hypothyroidism, masculinization, hirsutism, headache, dizziness, hypotension, pruritus, myalgia, and fever. The following classes of drug may interact with aromatase inhibitors when admin- istered concurrently : These products will interfere with the pharmacological actions of aromatase inhibitors. N (111) (49) 596 von Deutsch, Abukhalaf, and Socci is not intended to explain peculiarities of state law in these areas. Rather, it reports the law as stated in the drug interaction cases within the scope of this chapter. The reader is advised to seek local counsel in the jurisdiction in which an action is filed for a review of the law applicable to the action. The plaintiff’s physician had prescribed Isocet to the patient to treat his complaints of tension headaches in 1994 and 1995. In 1997, the patient was referred to an epilepsy specialist who prescribed Dilantin to control the patient’s sei- zures. The first physician was involved in administering and monitoring the levels of Dilantin. While taking the Dilantin, the patient experienced a tension headache and took two Isocet tablets from his earlier prescription, and shortly thereafter was diag- nosed with acute liver failure. The epilepsy specialist testified that she was aware of the medical risk of the interaction of Isocet and Dilantin, but still would have prescribed Dilantin because of the greater risk posed by the patient’s seizures. The court held that the plaintiffs failed to controvert this testimony, that the defendant manufacturers were shielded from liability under the “learned intermediary doctrine,” and that any failure to warn on the part of the defendants was therefore not the proximate cause of Mr. The plaintiffs had alleged that the defendant manufacturers had failed to label their products with adequate warnings of Dilantin’s propensity to interact with acetamin- ophen, placed defective and unreasonably dangerous products in the marketplace that caused Mr. Eck’s liver failure, and were negligent in the designing, testing, warning, and marketing of their products through their failure to provide adequate instructions or warnings, and by misrepresenting the safety of their products when used in conjunc- tion with one another. Applying Oklahoma law, the court reasoned that, in order to recover in a failure to warn case against a drug manufacturer, a plaintiff must establish both cause-in-fact (that the product in question caused the injury) and proximate cause (that the manufac- turer of the product breached a duty to warn of possible detrimental reactions, and this breach was a substantial contributing factor in causing the harm). Under Restatement (Second) Torts § 402A comment K, certain products, including prescription drugs, are “unavoidably unsafe products” that cannot be made completely safe, but serve a public benefit, so drug manufacturers cannot be held strictly liable merely because of the dan- gerous propensities of their products. Although the manufacturer has a duty to warn ultimate consumers of known dangers of prescription drugs and their interactions, there is an exception to this duty—the “learned intermediary doctrine”—under which the manufacturer is shielded from liability where the product is properly prepared and mar- keted and proper warning is given to prescribing physicians. The prescribing physician acts as a learned intermediary between the patient and the prescription drug manufac- turer by assessing the medical risks in light of the patient’s needs. No part of this book may be reproduced in any form, by photostat, microfilm, xerography or any other means, or incorporated into any information retrieval system, electronic or mechanical, without the written permission of Kaplan, Inc. Drugs for Inflammatory and Related Disorders Chapter 1: Histamine and Antihistamines 227 Chapter 2: Drugs Used in Gastrointestinal Dysfunction. Chapter 1: Anticancer Drugs 307 Chapter 2: Anticancer Drug Practice Questions 311 Sedion X: Immunopharmacology Chapter 1: Immunopharmacology 315 Chapter 2: Immunopharmacology Practice Questions. The Notes were designed to be accompanied by faculty lectures-live, on video, or on the web. To maximize the effectiveness of these Notes, annotate them as you listen to lectures. While these margins are occasionally punctuated by faculty high-yield "margin notes," they are, for the most part, left blank for your notations. Many students find that previewing the Notes prior to the lecture is a very effective way to prepare for class. It also affords you the opportunity to map out how the information is going to be presented and what sorts of study aids (charts, diagrams, etc. Pharmacokinetics Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distri- bution, metabolism, and excretion. The biodisposition of a drug involves its permeation across cellular membrane barriers. Absorption into Plasma Drug"Excretion Drug Metabolism (Renal, Biliary, (Liver, Lung, Blood, etc. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs; however, water solubility Can influence permeation through aqueous phases. Diffusion down a concentration gradient--only free, unionized drug forms contribute to the concentration gradient. The larger the surface area and the greater the vascularity, In A Nutshell the better is the absorption of the drug. Clinical Correlate ~ • Only nonionized forms undergo active secretion and active or passive reabsorption. Renal Clearance of Drug Modes of Drug Transport Across a Membrane Bridge to Physiology Table 1-1-1. Mechanism Direction I mechanisms are discussed No No No I in greater detail in Section Passive diffusion Down gradient! Facilitated diffusion Down gradient No Yes Yes Active transport Against gradient Yes Yes Yes (concentration! For some drugs, their rapid hepatic metabolism decreases bioavailability-the "first- pass" effect.

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Thus molecular mechanics uses an empirically derived set of simple classical mechanical equations buy 75 mg sildenafil amex, and is in principle well suited to provide accurate a priori structures and energies for drugs proven 25 mg sildenafil, peptides purchase discount sildenafil online, or other molecules of pharmacological interest purchase sildenafil in united states online. Molecular mechanics lies conceptually between quantum mechanics and classical mechanics, in that data obtained from quantum mechanical calculations are incorpo- rated into a theoretical framework established by the classical equations of motion. The Born–Oppenheimer approximation, used in quantum mechanics, states that Schrödinger’s equation can be separated into a part that describes the motion of electrons and a part that describes the motion of nuclei, and that these can be treated independently. Quantum mechanics is concerned with the properties of electrons; molecular mechan- ics is concerned with the nuclei, while electrons are treated in a classical electrostatic manner. The heart of quantum mechanics is the Schrödinger equation; the heart of molecular mechanics is the force field equation. A typical molecular mechanics force field is shown below: General form of a force field equation: V = Vr + Vθ + Vω + Vinv + Vnb + Vhb + Vcross (1. Typically, the bond stretching and bending functions are derived from Hooke’s law harmonic potentials; a truncated Fourier series approach to the torsional energy permits accurate reproduction of conformational preferences. A force field equation that has been empirically parameterized for calculating peptides must be used for peptides; it cannot be applied to nucleic acids without being re-parameterized for that particular class of molecules. Thankfully, most small organic molecules, with mol- ecular weights less than 800, share similar properties. Therefore, a force field that has been parameterized for one class of drug molecules can usually be transferred to another class of drug molecules. In medicinal chemistry and quantum pharmacology, a number of force fields currently enjoy widespread use. Molecular mechanics calculations are extremely fast and efficient in providing information about the geometry of a molecule (especially a macromolecule); unfortunately, molecular mechanics provides no useful information about the electronic properties of a drug mol- ecule. Quantum mechanics, on the other hand, provides detailed electronic information, but is extremely slow and inefficient in dealing with larger molecules. For detailed cal- culations on small molecules, high level ab initio molecular orbital quantum mechanics calculations are preferred. For a small molecule that is extremely flexible, one may wish to calculate many different conformations of the same molecule. For such a problem, a preliminary series of molecular mechanics calculations to identify a smaller number of low energy conformers, prior to performing a quantum mechanics calculation, may be indicated. At other times, quantum mechanics and molecular mechanics may be used together in harmony. If one wishes to use quantum pharmacology calculations to simulate a drug interacting with a site on a receptor protein, such calculations have both small molecule and large molecule components. The overall protein is studied using molecular mechanics calculations; however, the small region around the receptor site (and the drug interacting with that receptor via electrostatic interactions) is studied using ab initio quantum mechanics calculations. Regions intermediate between these two zones and at the interface between the molecular mechanics optimized region and the quantum mechanics optimized region may be studied using intermediate semi- empirical molecular orbital calculations. These two mechanics approaches provide a single energy for a single given geometry of the molecule; that is, they express geometry as a function of energy—this function defines an energy surface such that all possible geometries of the molecule are defined by a point on the energy surface. To obtain the optimal geometry, one must minimize the energy function (as defined by either the Schrodinger equation or a force field); that is, one must find the lowest point or deep- est well on the energy surface. This is a multi-dimensional problem complicated by the presence of many local energy troughs on the energy surface which are minima in a mathematical sense, but which are higher in energy than the one single global energy minimum. Many of the minimization algorithms in current use are based on either a steepest descent method or a Newton–Raphson method, which require first and second derivative information about the energy surface, respectively. The steepest descent method is superior if the starting geometry of the drug molecule under consideration is far from the global minimum on the energy surface. The Newton–Raphson method, on the other hand, is superior when fine-tuning the geometry of the drug molecule within the depths of the energy surface well. The two methods are frequently used in sequence, with the steepest descent method being used prior to final optimization by a Newton–Raphson method. For example, if the putative drug being studied is a hexapeptide, it will exist in a multiplicity of low energy shapes; the hexapeptide’s potential energy surface will have many, many low energy wells, and trying to identify the global energy minimum (the lowest energy well) is a challenging task. Such energy surfaces may have billions of low energy wells, and trying to identify the single lowest energy well is a computationally demanding problem. The multiple minima problem also explains our inability to predict protein folding when our only starting information is the primary amino acid sequence of a protein. There exist a number of techniques for addressing the multiple minima problem when trying to identify the lowest energy conformer for a flexible drug or for a recep- tor protein. These techniques are computational chemistry methods that enable one to “search the conformational space” of the floppy drug molecule or protein under study. The Monte Carlo method was one of the first methods used to search conformational space, having been adapted from classical statistical mechanics. Using this method, random moves are made to the rotatable bonds of an isolated molecule. Then, using a Metropolis sampling procedure, it is possible to generate a large number of suitable conformations. The spectrum of acceptable conformations is then energy minimized (using a quantum mechanics or molecular mechanics approach, as discussed above), and ranked by energy. Although it is necessary to generate a large number of confor- mations, in principle it is possible, within a user-defined timeframe, to achieve a repre- sentative sample from low-energy conformational space. A second, widely used method for searching conformational space is through mole- cular dynamics calculations. A simple definition of molecular dynamics is that it sim- ulates the motions of a system of atoms with respect to the forces that are present and acting on the molecule. This collection of forces causes the system to change, but by collective motion of atoms over time, in a way that is described by integrating Newton’s second law of motion (F = ma, where F is the force acting on an atom, m is its mass, and a is its acceleration). If one can calculate the next configuration of the collection of atoms, it is possible to follow the evolution of the atomic movements within the mole- cule over time. This is different from the Monte Carlo method, which requires outside intervention to produce change by a random move; in molecular dynamics, all changes result without external intervention and arise from within the system itself. In a molec- ular dynamics calculation, the molecule is “heated” by assigning velocities randomly to the atoms for a given temperature. Once the first velocities have been assigned, the mol- ecular dynamics simulation is self perpetuating. As the simulation of the atomic move- ments progresses, the new atomic positions are calculated. By “heating” the molecule and permitting it to cool, it is possible to explore the conformational space of the molecule, thereby identifying low energy shapes. The genetic algorithm method is a technique that has very recently gained attention for searching conformational space. Genetic algorithms may be applied to the multiple minima problem of molecular conformational analysis via a variety of methods. In one such method, the torsional angles within a given molecule are designated as “genes. If this offspring has a lower energy than its parents (as determined using either molecular mechanics or quantum mechanics calculations), the conformation is said to have “fitness” and is permitted to survive. The “most fit” conformations are permitted to propagate by exchanging their genes with their sibling conformers. A mathematical pro- cedure, termed a “mutation operator,” is used to incorporate greater diversity amongst the genes as successive generations are created. Genetic algorithm calculations permit families of low energy conformers to be identified. Monte Carlo methods, molecular dynamics calculations, and genetic algorithm meth- ods are all techniques for searching conformational space; each has strengths and weak- nesses. The techniques are complementary rather than competitive, and may be used together in a concerted attempt to identify low energy conformers of drug molecules. Since these methods are simply techniques for skipping across the conformational space of a molecule, they must be used in conjunction with a mechanics method (e. One final issue, which confounds the use of these methods for identifying the elusive global energy minimum, concerns the biological relevance of this lowest energy con- formation once it has been identified. Just because a detailed quantum mechanics cal- culation has identified a given conformation as the lowest energy shape for a drug molecule, this does not mean that this is the bioactive conformation. The interaction of a drug with its receptor is a dynamic process in which each molecule flexes to fit the other. It is entirely possible that the drug molecule may assume a higher energy con- formation (by several kcal/mol) in order to achieve this fit, thereby rendering the search for a global energy minimum somewhat irrelevant.

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