CHAPTER 1
Molecular Informatics: Sharpening Drug Design's Cutting Edge
Darren R. Flower
EDWARD JENNER INSTITUTE FOR VACCINE RESEARCH, COMPTON, BERKSHIRE RG20 7NN, UK
1 Introduction
The word 'drug', which derives from the Middle English word 'drogge', first appears in the English language during the 14th century and it has, at least during the last century, become, arguably, one of the most used, and misused, of words, becoming tainted by connotations of misuse and abuse. The dictionary definition of a drug is: 'a substance used medicinally or in the preparation of a medicine. A substance described by an official formulary or pharmacopoeia. A substance used in the diagnosis, treatment, mitigation, cure, or other prevention of disease. A nonfood substance used to affect bodily function or structure.' Even within the pharmaceutical industry, possessed, as it is, by a great concentration of intellectual focus, the word has come, in a discipline-dependent way, to mean different things to different people. To a chemist a drug is a substance with a defined molecular structure and attributed activity in a biological screen or set of screens. To a pharmacologist a drug is primarily an agent of action, within a biological system, but typically without a structural identity. To a patent lawyer it is an object of litigious disputation. To a marketing manager it is foremost a way to make money. To a patient – the pharmaceutical industry's ultimate end-user – a drug is possibly the difference between life and death.
Unmet medical need is, then, a constant stimulus to the discovery of new medicines, be they small molecule drugs, therapeutic antibodies, or vaccines. This unmet need has many diverse sources, including both life-threatening conditions – such as arise from infectious, genetic, or autoimmune disease – and other conditions that impinge deleteriously upon quality of life. The division between the causes of disease is seldom clear cut. Genetic diseases, for example, can be roughly divided between those resulting from Mendelian and multifactorial inheritance. In a Mendelian condition, changes in the observed phenotype arise from mutations in a single dominant copy of a gene or in both recessive copies. Multifactorial inheritance arises from mutations in many different genes, often with a significant environmental contribution. The search for genes causing Mendelian disorders has often been spectacularly successful. Multifactorial diseases, on the other hand, have rarely yielded identifiable susceptibility genes. The identification of NOD2 as causative component for Crohn's disease has been hailed as a major technical breakthrough, leading, or so it is hoped, to a flood of susceptibility genes for multifactorial diseases. Unfortunately, the mode of inheritance in many multifactorial diseases is probably so complex that the subtle interplay of genes, modifier genes, and causative multiple mutations, which may be required for an altered phenotype to be observed, will, for some time yet, defy straightforward deduction.
Heart disease, diabetes, and asthma are all good examples of multifactorial disroders. Asthma, in particular, is, arguably, one of the best exemplars of the complex influence of environmental factors on personal wellbeing. It is a major health care problem affecting all ages, although it is not clear if the disease is a single clinical entity or a grouping of separate clinical syndromes. Asthma is a type I, or atopic, allergic disease, as contrasted with type II (cytotoxic), type III (complex immune), or type IV (delayed type). The word 'asthma', like the word 'drug', first appears in English during the 14th century. It derives from the Middle English word asma: a Medieval borrowing from Latin and Greek originals, although the incidence of allergic disease has been known since ancient times. It is a condition marked by paroxysmal or laboured breathing accompanied by wheezing, by constriction of the chest, and attacks of gasping or coughing. It is generally agreed, that, over the past half-century, the prevalence of asthma, and type I allergies in general, particularly in western countries, has increased significantly. The reasons for this are complex, and not yet fully understood. Clearly, improvements in detection will have made a significant contribution to the increased apparent incidence of asthma, and other allergies, as is seen in many other kinds of condition, although this will only make a partial contribution to the overall increase. Other causative factors include genetic susceptibility; increased allergen exposure and environmental pollution; underlying disease; decreased stimulation of the immune system (the so-called hygiene or jungle hypothesis); and complex psycho-social influences. This final class includes a rich and interesting mix of diverse suggested causes, including the increasing age of first time parents, decreased family size, increased psychological stress, the increase in smoking amongst young women, decreases in the activity of the young, and changes in house design. The last of these, which includes increased use of secondary or double glazing, central heating, and fitted carpets has led to a concomitant increase in the population of house dust mites such as Dermatophagoides farinae and Dermatophagoides pteronyssinus, which are believed to be key sources of indoor inhaled aero-allergens.
Amongst the rich, developed countries of the first world – the pharmaceutical industry's principal target population – some of the most pressing medical needs are, or would seem to be, a consequential by-product of our increasingly technologized, increasingly urbanized personal lifestyles. These include diseases of addiction or over-consumption, those that characterize the West's ageing population, and those contingent upon subtle changes in our physical environment.
Certain diseases have increased in prevalence, while the major killers of preceding centuries – infectious diseases – have greatly diminished in the face of antibiotics, mass vaccination strategies, and improvements in hygiene and public...
