Drug discovery is a complex process and is multidisciplinary in nature. Up to mid twenty first century, the process of drug discovery is considered conventional as the concept of the molecular targets was yet to develop. As the understanding of the human genome and genomic basis of the disease pathogenesis advanced, scientists all over the world used it as a path for drug discovery.
In this new era, the outcome of the drug discovery is faced with challenges such as poor turnover of the successful drug candidates and huge investment in terms of 'money' and most crucially the 'time' to develop a single molecule.
Today, new drug discovery has become a disciplined approach, where scientific input is given since inception of the disease targets. One of the major challenges that pharmaceutical companies still facing is investment in terms of money and time. The technology is a knowledge drive for the drug discovery which can accelerates the pace at which the experimentation can be sought. The type of technology that is used for drug discovery decides the time for drug development starting from receptor mapping, lead identification - lead optimization, pharmacodynamic screening, pharmacokinetic optimization, pre-clinical assessment to clinical assessment of the drug.
Traditionally in this scientific world, a new field of science and technologies emerge to facilitate the development of new inventions of scientific and technological approaches, various experimental tools and devices.
NANOSCIENCE & NANOTECHNOLOGY
An inevitable consequence of modern technology has been a mounting trend towards the miniaturization of components. Today we are living in an era where the forefronts of both engineering and scientific ventures have reached the length scale of nanometers. This has led scientific community to device a distinct discipline which is an amalgamation of various streams of the science and eventually accepted as "nanoscience and nanotechnology". Today, these two are rapidly growing fields of research in chemistry, physics and biology with comprehensive insinuation for new technologies. These disciplines stretch across the whole spectrum of science touching medicine, physics, engineering and chemistry etc. It represents a new frontier in science and technology with long term goals and benefits. Nanotechnology is a technological revolution of the 21st century that will greatly benefit and change the nature of scientific thought process and has promise for accelerating the drug discovery process.
NANOTECHNOLOGY AND DRUG DISCOVERY
In present scenario, pharmaceutical companies have common technology platforms for drug discovery, worldwide. These modern technologies include cloning and expression of specific receptors, combinatorial chemistry derived compound libraries with high-throughput, automated screening. Scientific advancements in the fields of genetics / genomics and invention of bioinformatics have explored the relationship between the diseases and gene products which are useful tools in identification of new targets for a number of diseases. This process of drug discovery still has limitations such as lack of information needed to improve target selection and validation, precise and rapid screening techniques. Nanotechnology, although cannot provide the decisive resolution to all these problems. However, nanotechnology and nanoscience can provide tools that can play an important role in drug discovery.
NANO-ENABLED TOOLS FOR PRECISE AND SPEEDY DRUG DISCOVERY
As forecasted by nanomarket's report, nanotechnology can provide substantial benefits to the drug discovery process by improving understanding of materials / chemicals at the cellular/molecular level, enhanced detection and substantiation of target proteins and promising candidate drugs, increased throughput, shorter time for the discovery of new drugs, precise use (nanoliter scale) of precious reagents required to carry out screening of potential drugs etc. Nanoscience and nanotechnology also can help the drug discovery process by providing miniaturization, mechanization, momentum, and steadfastness to various drug discovery processes.
i). Nanocrystals / nanoparticles: Existing drug discovery techniques face problems related to target selection where poorly validated targets fail in discovery or in clinical development. Secondly, it also faces limitations in lead identification or optimization. Bioimaging is crucial technique in identifying and mapping potential drug targets. Nanocrystals are nanometer-sized semiconducting materials that are neither atomic nor bulk semiconductors which have shown promising usefulness in various bioimaging techniques and are having advantage in terms of quality and sensitivity as compared to conventionally available fluorescent organic dyes.
Various types nanocrystals used in bioimaging are;
a) Quantum dots (QDs): QDs are nanometer-sized semiconducting materials. QDs have bright fluorescence, narrow emission, broad UV excitation and high photostability. QDs enable the tagging of a variety of different biological components like proteins or different strands of DNA with specific colors. These are designed to bind with and illuminate individual biological targets of choice such as genes, nucleic acids, proteins, cancer cells, and even entire blood vessels.
b) Gold colloids: Gold nanoparticles can be used for detection of genetic sequence in solution and other genetic applications. Due to their surface functionalization ability, they can also be used for drug discovery applications as an alternative to QDs.
c) Nanoshells: Nanoshells are gold-layered dielectric nanoparticles. Nanoshells can carry molecular conjugates to the antigens that are expressed on the cancer cells themselves or in the tumour microenvironment. These nanoshells can also be used in detection of immunoglobulins in whole blood.
Nanoparticles offer great potential in biology and medicine research. Potential concern of nanocrystals use in drug discovery would be their total size.
ii) Nano Mass Spectrometry: Mass spectrometry (MS) is used for the accurate determination of molecular masses in structural determination of chemical compounds. Mass spectrometry is most suitable for the analysis of pure proteins or very simple mixtures. Recent breakthrough in protein analysis is development and refinement of 2 dimensional gel electrophoresis (2DE), which separates proteins from one another so that they can be studied individually. Viable alternative approach to 2D gel electrophoresis is chromatographic separation of peptides with electrospray ionization (ESI)-MS or tandem MS (MS/MS) detection. Conventional ESI-MS analysis has limitation in terms of its high sample requirement. Nanotechnology enabled development of nano-electrospray (ES) mass spectrometry which contains an array of nanoelectrospray nozzles, each one-fifth the diameter of a human hair, etched in a silicon wafer, has an advantage in terms of its sample size requirement. This particular technique has high applicability in the fields of analysis of neurosteroids and related molecules, analysis of peptides at the subpicomole level, where the availability of sample is a limitation for scientific experimentation.
iii) Nano-Arrays: Microarrays are defined as a substrate and surface chemistry onto which a biomolecule or capture agent has been immobilized for expression analysis and functional characteristic. Microarray is a useful platform technology with major applications in genomic research and drug development. This technology has wide applicability in analytical investigation and characterization of proteins (proteomics), carbohydrate structures (glycomics) and the investigation of cell idiosyncrasies (cellomics). Presently accessible microarray technologies experience certain limitations that proscribe their exploitation for drug discovery applications.
b) Near-field scanning optical microscopy (NSOM): It is a type of microscopy where a sub-wavelength light source is used as a scanning probe. In recent times, attention has been paid to scanning probe microscopy (SPM) techniques for scrutinizing biological samples. SPM has many advantages for the study of mechanical, structural and functional properties of biological samples as well as for acquiring high-resolution topographic images. NSOM is a type of SPM which allows spatial resolution with more than an order of magnitude improvement over the pre-eminent conventional optical methods, including laser scanning confocal microscopy. SNOM imaging has been applied to many kinds of biological samples, such as DNA or proteins, whole cells and chromosomes. SNOM is particularly useful in labeling cell surface membrane proteins, since the illumination depth is limited to tens of nanometers. This particular technique allows good discrimination among proteins on the cell membrane and those present in the cytoplasm.
c) Surface Plasmon Resonance (SPR): Surface plasmons are electromagnetic waves which propagate at optical frequencies on the interface between a metal and a dielectric field. Their wavelength is extremely sensitive to any chemical change at the interface which will dramatically change their properties. SPR is a non-destructive analysis technique which is useful in investigating thin layers of molecules upon a material surface. SPR can detect changes in refractive index (n) occurring near the surface of a metal (within ~200nm). The recent development of SPR based biosensor technologies for biospecific interaction analysis (BIA) facilitates the monitoring of a variety of molecular reactions in real-time. Combinations of SPR based BIA combined with MS has potential role in proteomics and developing technology to design and develop efficient drug delivery systems. SPR is also used in studies involving molecular interactions between transcription modifiers and target biomolecules.
It is evident from the new frontiers made available by the nanotechnology that newer methodologies are likely to be important in the efficient and speedy drug discovery. Scientists of different disciplines from all over the world are involved in numerous areas of nanotechnology including the synthesis of inorganic, organic and hybrid nanomaterials for use in nanodevices, the development of novel nano-analytical techniques, the manipulation of biological molecules such as DNA and the evolution of molecular machines. The future applications of nanotechnology could be immense and varied in the process of drug discovery.
- (The author is with Pharmacy Group, Birla Institute of Technology and Science, Pilani, Rajasthan)