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Drug discovery and development grew into a wide interdisciplinary field during the last decades. The current state of pharmaceutical drug discovery and development (DDD) estimates that only up to ten compounds out of a thousand screened hits would result in optimized leads and enter preclinical testing, with a chance of 9.6% to pass the clinical testing phase. The drug development phase starts with preclinical testing followed by the clinical stage comprising phase I-III human trials. Starting from the generation of a lead compound assessment, optimization of pharmacokinetic properties and correlation to pharmacodynamic effects increases in importance as one of the three major attrition causes among toxicity and efficacy.
In a long ongoing effort, more and more in silico techniques are being integrated into several points of DDD with different purposes. In silico techniques can ease the process of SAR assessment as well as the generation of compound series by guiding combinatorial chemistry since they allow fast and easy evaluation of compounds before synthesis from big libraries. In silico ADME prediction aims to generate tools and models based on experimental data to calculate in vivo behavior of compounds by finding quantitative structure-property relationships (QSPRs), which connect structural information to physical and chemical characteristics or even biological behavior.
When using in silico methods for prediction, it is important to keep in mind that algorithms and tools applied are only models thus being only as good as the data and idea they are based on. As a result of newly achieved advances in computational capability, more complex models and algorithms can now be applied. Despite this, it is still a challenge to create a model for the pharmacokinetic and pharmacodynamic phenomena and interactions within an organism as complex as a mammal, let alone humans.
By combining various techniques, the modern pharmaceutical analyst hopes to achieve the goal of pooling the virtues of each technique to establish purity and identity. Currently, MS combined with different chromatographic methods, provides some of the most powerful techniques available for pharmaceutical analysis. Combined HPLC-NMR spectroscopy is another rapidly growing technology, enabling the rapid and detailed structural characterization of complex mixtures. HPLC-NMR, as well as HPLC-NMR integrated with MS (HPLC-NMR-MS), have been applied to drug discovery, especially in the separation and structural elucidation of drug impurities, reaction mixtures, degradation products, in vitro and in vivo metabolites, and combinatorial library samples.
Fig.1 Examples of combination analytical techniques. (Koh, 2003)
HTA is a methodology aimed at the rapid analysis of large numbers of compounds. This field has been expedited by the requirement to provide analytical support for multiple drug targets emerging from the field of molecular biology, human genetics, and functional genomics. HTA is having an increasingly important role in early-stage drug development, providing a qualitative and quantitative characterization of compound libraries and bioanalytical support for preclinical and clinical ADME studies.
Fig.2 Summary of HTA techniques. (Koh, 2003)
MS is currently the method of choice for compound characterization because of its selectivity, sensitivity, resolution, sample throughput, and capability of sample identification and structure elucidation. High throughput and ease of automation render it one of the most useful MS-based techniques for the characterization of compound libraries. Although data interpretation is more time-consuming compared to MS, NMR is also being developed as a key high-throughput technology by the use of automation and computerization for sample-changing. In the pharmaceutical industry, high-throughput NMR-based screening is emerging as a useful tool for high-throughput structural characterization of protein-ligand interactions, aiding the identification of compounds that bind to specific protein targets.
Fig.3 Applied fields of modern pharmaceutical analysis in drug discovery. (Koh, 2003)
Creative Biolabs’ visionary team has been at the forefront of drug discovery and development for over a decade. We provide powerful risk-based preclinical data verification services for drug research and development. We are an exceptional team of drug development experts. Our leadership team, board of directors, and scientific advisory board have vast experience in the discovery, development, regulatory approval, and successful commercialization of a wide range of drugs. If you are interested in our services, please feel free to contact us for more information.
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