Drug screening: A novel perspective

New technologies offering comprehensive solutions to drug screening are rapidly coming up as companies vie for finding an improved or a novel molecule, says A N Nagappa

The search for novel therapeutic leads is an evergreen segment in the field of research with very high stakes. Drug screening in recent times has not only become high tech but highly intense. The survival of industries worldwide depend upon patents of the research leads that can be converted into a marketable product is very much evident. The pharmaceutical industry, university departments and independent researchers are leaving no stone unturned in finding a new therapeutic lead and products on all therapeutic fronts. From analgesics to antibiotics, from antidepressants to analeptics, the vivid varieties of therapeutic categories are screened in a competitive manner to come out first in finding an improved or a novel molecule.

Changing disease pattern

Interestingly, the changing dynamic patterns of diseases are also galvanizing the research activities. For example changed morbidity and mortality of multi-drug resistant tuberculosis, HIV, drug resistant typhoid and metabolic disorders like diabetes mellitus are becoming problems of the modern society with involvement of very large population. There is an urgent need to attend these problems by finding effective drugs and methods to bring them under control.

Apart from this the hidden serious side effects of the drugs during clinical trials are surfacing when used extensively in the community. For example nimesulide hepatotoxicity; The drug regulatory authorities are very much concerned and are under consideration of banning the nimesulide as a general analgesics; withdrawal of a promising anti-diabetic roziglitozone during clinical studies. Pharmaco-surveillance has become an important activity to study the surfacing of adverse drug reaction during usage in the community. This has given a fillip to the drug discovery from the product development front.

Patient-friendly drugs

Another emerging area that is strongly stimulating the drug discovery is development of products, which are patient-friendly. Conventionally, most of the pharmaceutical products are developed with less emphasis on patient compliance leading to lot of inconvenience to the patient. Termination of regimen of the therapy is a serious problem in treatment of serious disease like tuberculosis and chronic diseases. Hence, there are numerous examples of development and screening of novel drug delivery systems with improved patient compliance.

The conventional mode of screening for new molecules would involve synthesis and search of natural resources like plants, animals and soil samples. However, the novel synthetic molecules are the major source for drug molecules. The quest for ideal molecules in all therapeutic fronts is so intensive, that it has lead to invent new technologies to meet the demand.

Mechanised technology

Bioinformatics, computational chemistry, qsar studies, rDNA technologies, hybridoma technologies, receptor technology, human genomic, proteomics and transgenic animal models are in fact developed to rationalize the drug screening methods. Recently, the convergence of above technologies is leading into an efficient robust mechanized technology for primary screening of molecules for activity.

After inventing the combinatorial chemistry that can synthesize very large number of molecules at about 10,000 varieties of congeners in a stroke, a complimentary technology to match was also invented to identify the possible therapeutic activity for e.g. high throughput screening. The high throughput screening is basically primary screening technology comprising of in vitro testing of large number of molecules by robotics.

The model would identify the key enzyme responsible for therapeutic action. For example, anti-HIV drugs can be screened by studying the inhibitory action of the molecules on key enzymes of HIV like integrase reverse transcriptase and protease. Similarly anti-hypertensive can be screened by studying inhibitory action on angiotensin converting enzyme. Drugs of antidepressants can be studied by studying the activity on MAO enzymes.

Drug screens

Recently technologies are being developed which offer comprehensive solutions to drug screening. They are popularly known as drug screens. Drug screens are nothing but workstations comprising of designed miniature plates in which in vitro drug testing is done with the aid of robotics. The outcome of biochemical reactions is followed precisely by sophisticated analyzing instruments like UV, FTIR, FT mass spectroscopy and HPLC. Drug screens are in fact microtitre plate with wells in them in which the biochemical reaction would take place.

Initially microtitre plates with 96 wells were offered. After some time 384 well plate had become standard, which can screen 384 molecules at a stroke. Amersham Biosciences based in Piscataway, New Jersey, one of the leading manufacturer of screening platforms, has come out with an portable screening equipment called LEAD seeker which has platforms of 96, 384 and 1536 wells. Some of them have got as high as 3456 wells. LEAD seeker uses imaging technology based on charge-coupled device that detects fluorescence and luminescence. LEAD seeker is considered as a significant improvement as it uses florescence based assays in place of radio bioassays which have better quality of results than scintillation assays.

The industry requirements are so diverse that general instrumentation like above would suffice their need. Each industry wants to built its own customized facility of screening to match its requirement. Hence there are companies, which offer turnkey solutions with software and bioinformatics solution package supported for screening.

The drug screens can be used mainly for primary screening, however, the major aspect of drug development like drug toxicity, pharmacokinetic profile, drug efficacy and clinical trials remains the task ahead of drug development. One major drawback of these type of screens is that a drug molecule in system interacts with variety of bio-molecules and exhibits its pharmacological actions, where in drug screen simple one to one interactions are relied upon to screen an activity.

The writer is with Pharmacy group, Birla Institute of Technology and Science, Pilani, Rajasthan