Drug Discovery and Design : Present Scenario
By - 10/14/2005
Mr. Aniruddha V. Dadke
For centuries the art of medicine has been dominated by bumps, bruises,
or other symptoms, felt by the patient or discovered by the physician, with
eyes ever-magnified by increasingly sophisticated scanning technology: the microscope,
the x-ray, and eventually the MRI. But however powerful the machine, the
underlying model remained the same. To find the illness, the health professionals
first had to look for the symptom. To diagnose the cancer, they had to
see the tumor. To find a drug, they had to undergo a long, costly, and
laborious process of trial and error, trying millions of natural compounds on
animals to find one that seemed to work.
This approach to medicine may be coming to an end. As drug discovery becomes an information-based science, speeded by rapid increases in computer processing power and the marriage of test tubes with microchips, pharmacists are transforming the way one can diagnose and treat many of the worst human diseases. New drugs currently in clinical trials are no longer scattershot one-size-fits-all affairs, but carefully targeted to the molecular fingerprints of specific diseases. Some of these drugs are even targeted to a patient’s unique DNA profile. In a breathtaking paradigm shift, medicine is moving from the species level—the ingrained assumption that drugs and diseases work the same in all human beings—to the individual level, unlocking new healing possibilities in the minute differences between seemingly similar diseases and their individual victims. The result will be a new age of medical therapy, dominated not by cell, tissue, and organ replacements but by early diagnosis and individualized drug treatments[1].
Remarkable progress has been made during the past five years in almost all the areas concerns with drug design and discovery. A limited survey of the literature reveals no less than 140 review articles published to date with the phrase “drug discovery” in the title or abstract an increase of more than 150% from just five years ago. Hence, it may seem redundant to compile still another, but the pace at which this field has progressed justifies continuous updates of advancements in new techniques and therapeutic successes. Therefore, this review will concentrate on the literature of primarily the past five years, adding historical information for appropriate perspective. An attempt has been made to answer three basic questions concerning the many disciplines related to the drug design and discovery process: 1) What is the state-of-the-art in drug discovery today? 2) What are the latest tools used in the drug discovery process, and 3) Where is drug discovery going in the new millenium? Many very recent reviews have also addressed these questions [2-4].
LESSONS FROM THE PAST
It may be useful to offer a very brief summary of some of the historical approaches to drug design and discovery to learn from whence this “art” has evolved. It is impossible to trace the roots of drug discovery to their true origin. Many ancient populations made reports the medicinal properties of various plant extracts and elixirs, all a result of a necessary trial and error search for remedies of specific ailments [5]. Nature has been and still is the single most important source of drugs or drug precursors [6]. Although natural products such as morphine, cocaine, salicylates, atropine, quinine and digitalis are all considered, so to speak, “ancient”, in the 21st century, these natural products and their derivatives remain as useful therapeutics even today, in some cases, thousands of years after their original “discovery”. So from early civilizations, man has used nature to heal or soothe specific ailments. Unwittingly, the use of extracts and whole plants as remedies amounted to the administration of several chemical entities at once, whose constitution and synergism was wholly unknown. It was not until the 19th century when techniques for partitioning some of these extracts into individual components did single entity drugs become available.
Since the early 20th century, thoughts about drug action and mechanism expanded as the analytical techniques of biology, chemistry and pharmacology progressed. Discoveries of different families of therapeutics followed the seminal observations of Ehrlich, and after 1910, a new era in drug discovery emerged. Science saw the development of many drugs discovered hundreds of years earlier. Although quinine was found by early explorers to be used by Indians of South America, it was not isolated until 1823 and development of analogues as antimalarials began in the early 1900's [7]. New medicines such as antihistamines, trypanocidals and several important alkaloids, many extracted in the 19th century, were being synthesized and developed into commercial entities. The age of antibiotics began just prior to that famed serendipitous discovery of a crude penicillin culture by Fleming, with the discovery that a dyestuff (Prontosil) could cure gram-positive bacterial infections in man [8] The active component, sulfanilamide, paved the way for the development of sulfa drugs. The intensive study of Fleming’s original molds by Florey and Chain in the early 1940s showed that there was a mixture of several components in the penicillin preparation and these were separated, tested and more active constituents were found and developed into the first anti-infectious agent. Around this same time, more extensive development of antihisatmines, analgesics, barbituates, hormones (e.g., epinephrine), sedatives, hypnotics and antidepressants was seen in the 1940s-1950s. The improvement in chromatographic and diagnostic (detection) techniques as well as advances in synthesis and understanding of chemical principles accelerated the discovery of new drug entities in the second half of the 20th century. Another case of serendipity led to the discovery of Librium in 1957 [9] and later to the benzodiazepines class of antianxiety medications, which include Valium and Xanax. Valium was once the best-selling prescription drug in America. In addition to small molecule therapeutics, the 20th century saw the rise and success of vaccines to cure several bacterial diseases such as tetanus, diptheria, yellow fever, measles, mumps, rubella and polio. Diagnostic techniques such as X-rays, electrocardiograms, CT and PET scans, ultrasound and MRIs were all products of the last 40-50 years, and each technique played its own role in the design and development of new drug entities.
THE NEED FOR NEW PARADIGM
The competitive nature of the pharmaceutical industry and the high costs associated with drug development has placed great demands on improving the efficiency of drug discovery. This in turn has created a need for a new paradigm that enables more scientists to use structural information in the combinatorial chemistry and medicinal chemistry process. In the past, the only direct access chemists had to three-dimensional information was through physical models or a molecular modeling group. Chemists could build and twist plastic models in an effort to explore molecular conformations and similarities, but this was not very practical for everyday use. The other approach of using molecular modelers worked if one could get their attention and had plenty of time.
Both of these approaches limited the amount of information a chemist could use to develop leads, although they were qualified and interested in taking a more analytical approach.
PRESENT SCENARIO
In this section we will attempt to highlight the recent changes that have shifted the paradigms of drug discovery to what could be called the second “golden age” of therapeutic design. Our goal is to list and expand upon the various steps that are being followed today when initiating a new drug discovery program. Along the way we will focus on the more novel and exciting techniques that we feel will have impacted the drug discovery field most powerfully in recent years.
Selection and validation of novel molecular targets have become of paramount importance in light of the plethora of new potential therapeutic drug targets that have emerged from human gene sequencing. In response to this revolution within the pharmaceutical industry, the development of high-throughput methods in both biology and chemistry has been necessitated. With many of these key components of future drug discovery now in place, it is possible to map out a critical path for this process that will be used into the new millennium.[10]
The five major areas of modern drug discovery and design programs are,
1) Target Identification - The ability to sequence a genome and identify every expressed gene will lead to the identification of thousands of new targets, many of which will be relevant to the onset and persistence of disease. With the advent of proteomics and high throughput protein profiling information we will eventually reveal the role, function, structure, gene location, biochemical pathway, molecular interactions, and expression levels of each and every protein coded for by a particular genome. Therefore, the impact of recent progress in molecular biology and, in particular, of genomic sciences on drug discovery will change the course of this field remarkably. In fact, at present in most major pharmaceutical companies, 10% to 25% of new discovery projects are based on genomics [11]
2) Target Validation - Target validation, the process of determining that a molecular target is critically involved in a disease process, is a key activity in the drug development process. An important step in the clinical translation of identified targets involves pharmacological screens and tests in disease models to confirm a targets’ therapeutic potential [12]
3) Lead Identification - Lead is defined as a compound (usually a small organic molecule) that demonstrates a desired biological activity on a validated molecular target. To fulfill the criteria of what the industry considers a useful lead, the compound must exceed a specific potency threshold against the target (e.g., < 10 µM inhibition). The compounds used as potential leads could come from many sources. A majority of leads discovered in very recent programs are derived from a collection that is now referred to as a “library”. These may take the form of natural product libraries, peptides libraries, carbohydrates libraries, and/or small molecule libraries based on a variety of different molecular scaffolds. This issue of exploring the correct mix of diversity space while maintaining “drug-like” qualities is critical to the development stage of any new drug and is a central thrust of large drug discovery programs today [13].
Six major areas that have revolutionized the identification phase: 1) Virtual screening, 2) Informatics, 3) Advances in pharmacaphore mapping, (viz., database searching, modeling), 4) High throughput docking, 5) NMR-based screening and 6) Chemical genetics.
4) Lead Optimization – Once a lead compound is established in the identification process, the medicinal chemist will work closely with molecular pharmacologists to optimize the desirable traits of the lead. This process can be relatively fast since history has taught the medicinal chemistry community how to manipulate molecules to improve activity. Starting with intuitive structural modification to the development of structure-activity relationship (SAR) and quantitative SAR (QSAR) one can gain tremendous information. In addition Computer-aided drug design (CADD) or structure-based drug design (SBDD) has made a considerable contribution to the field of drug candidate optimization, and has been the subject of numerous reviews and books [14,15].
5) Preclinical Pharmacology and Toxicology - It is becoming clear that successful prediction of drug-like properties at the onset of drug discovery will payoff later in drug development. Therefore, there is increasing demand to design computer programs that can accurately predict physicochemical parameters [16]. Such parameters include oral absorption, blood-brain barrier penetration, toxicity, metabolism, aqueous solubility, logP, pKa, half-life, and plasma protein binding [17, 18,19-21].
Functional genomics and proteomics have been quite successful in
identifying functions of potential therapeutic targets such as encoded proteins.
In fact, the possibilities of identifying more than 10,000 novel target antigens
in the human genome may accelerate the discovery of new drugs and therapeutic
molecules[22].
FUTURE PERSPECTIVES
The enormous progress in the development of new methods in the field of molecular biology and computer science is currently unprecedented. The drug discovery process is no longer limited to the organic chemist who tinkers with a known structure to fine tune an activity: Drug design and discovery is a multi-disciplinary field where the scientist may soon be able to construct a virtual drug with all the desired chemical, physical and biological properties to survive the rigors of clinical testing-all before doing a single chemical reaction. Drug design and discovery in the postgenomic era is shattering old paradigms and routinely reconstructing the drug discovery protocols by including the eons of information encoded in our genome. These data may be used to rationally construct a drug “blueprint” for each individual for tailored therapy based on our genetic makeup. Genomics-related technology facilitates the elimination of unfavorable products at earlier stages of development than is currently possible. It also could guide companies in designing clinical trials that would more definitively prove drug efficacy, in turn decreasing the time, costs, and risks of drug development. In the clinical setting, pharmacogenomics will help physicians to better define the long-term health risks that patients face, more precisely diagnose the stage of patients' diseases, and more accurately predict their responsiveness to specific drugs or the likelihood for adverse events.
One could have never imagined this only a few short years ago, but the future will be in proteomics and emerging fields like chemogenomics and metabonomics.
References:
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About Authors
1. Mr. Aniruddha V. Dadke * (M.Pharm Pharmchemistry),
Lecturer – MAEER’S MIP, Kothrud, Pune – 38, Maharashtra,
India. Phone No - 020 25431795 (off.) 9850741643 Email – avdadke@rediffmail.com
* Author for corresopondance
2. Ms. Minal .S Kulkarni (M.Pharm Pharmchemistry),
Lecturer – STE’S Smt. Kashibai Navale College
of Pharmacy, ondhwa, Pune – 48, Maharashtra, India. Phone
No - 020 26931322 (off.) 9850190499