Challenges and Opportunities
4.2 MODELS OF HUMAN DISEASE BIOLOGY .1 Target-Based Drug Discovery
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4.2 MODELS OF HUMAN DISEASE BIOLOGY
referred to as those that possess recommended attributes associated with successful drug candidates. Most often, individual molecules that hit a useful set of multiple targets are chosen [5–7]. Since the completion of the Human Genome Project, target-based drug discovery has dominated modern phar- maceutical research due to its complementary advantage over phenotypic drug discovery.
Determining the network for complex diseases is challenging. For ex- ample, no single gene has been identified as the only cancer gene. A typical cancer patient would have several mutations in up to 300 genes, which is a daunting complexity for the medical researcher [8]. Also there is multiplica- tion of false positives, a common experience in studies of this nature [9].
Target Drug Discovery (TD2) was established for the screening of ex- ternal molecules in target-based assays to find compounds with therapeu- tic potential and collaboration possibilities [10]. It was pointed out that a target-centric approach for first-in-class drugs without optimization of the mechanism of action might lead to failure and a drop in productivity [11].
Some of the problems with target identification is that it has not com- pletely optimized the number of druggable targets with well-defined active sites that could be manipulated or inhibited with small molecule drugs.
Targets might be acting as transcription factors, structural components of key complexes inside the cell, or with unknown function. This is leading to a shift in focus toward a more direct drug discovery approach involving screening of compound libraries through phenotypic assays.
The following are target areas for drug development:
• Central nervous system – Alzheimer’s disease, Parkinson’s disease, affec- tive disorders
• Cardiovascular and metabolic diseases
• Atherosclerosis/thrombosis, type 2 diabetes, obesity
• Oncology – tumor growth molecules, cell signaling receptors
• HIV/AIDS – targets in viral lifecycle
• Infectious diseases – hepatitis B and C
• Autoimmune and inflammatory diseases – multiple sclerosis, arthritis, psoriasis, inflammatory bowel disease
• Asthma, chronic obstructive pulmonary disease (COPD)
4.2.2 Phenotypic Drug Discovery
Disease phenotype is based on signs and symptoms of disease mechanism or pathogenesis. Some diseases are easier to detect than others because the causative organisms can be easily known. A typical example is infections.
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For a drug company to pursue research in this area, epidemiological data of the morbidity and mortality are taken into consideration, linking the phenotype to a genotype. This normally begins by discovering the organs or tissue involved and a measureable function to discern change of activity, followed by finding the malfunctioned protein and other biomolecules that drive these chemical and electrical signals through body cells; their activities provide the first line of information used in the design of small molecules that interact with the drug target. Some examples are receptors, ligands, small molecule hormones, neurotransmitters, peptide hormones, growth factors, cytokines, trophic factors, vitamin D, chemokines, steroid hormones, retinoids, neuromodulatory peptides, thyroxin, and cortisol.
The phenotypic screen is usually more physiologically relevant since cells that are intact in their natural environment are used. Primary hits iden- tified in this process could target different types of proteins such as recep- tors, transcription factors, enzymes, and the signaling pathways. The finding of the associated molecules could help the tracing of the cell mechanism, and the upregulated or deregulated proteins along the biological network or pathway. This phenomenon has been instrumental in the discovery of many drugs but without the knowledge of their mechanism of action [12].
Certain therapeutic areas are more prone to phenotypic screening like in- fectious and the central nervous system diseases whereas target based areas are more aligned with oncology. Thus, no method could be universally ap- plicable as every format has its niche. However, most new molecular enti- ties were discovered through target-based screening. Through case study analysis, among several key considerations for selecting a therapeutic area or need is the unmet medical need, based on clinical manifestations like symptoms reported or observed, what populations are affected, progression of the condition, and the severity of the disease based on literature or clini- cal reports. Decision is informed by obtaining information about alterna- tive therapies, compliance and tolerance, evidence, and the strength of the information accrued.
The phenotypic-centered approach does not include disease mechanism studies since the screening assays could generate a good readout if properly designed [13] and the outcomes of which could lead to prototype design when establishing the structure–activity relationships. These are more suit- able for the discovery of drugs for rare diseases and neglected diseases, being a rather faster approach to save time and cost as the pharmacological prop- erties of the drugs are known. The obtained information can be used for a new drug development program following the validation of a new target. In
this regard, the current trend is redirecting efforts toward phenotypic drug discovery [14]. The Big Pharma is seeking to invite academic and biotech professionals for collaborations. The Lilly-sponsored Phenotypic Drug Dis- covery (PD2) initiative was established for the screening of external mole- cules in phenotypic modules to find compounds with therapeutic potential and collaboration possibilities [15].
4.3 DISEASES CONSIDERED IN BIOPHARMACEUTICAL