Introduction: (Principles of early drug discovery, 2014)
Biological targets are generally proteins or protein products which are directly related to the medical illness or a condition which needs to be treated and can be achieved by interaction with small molecules showing therapeutic effect. Small molecules interact with the biological target to produce desired beneficial effects. Biological target can be identified or selected based on the disease or medical condition which requires treatment. If a disease is related to an organ it can be predicted that the biological target may be present on the organ thus the organ can be a target organ. Further research about the exact location of the biological target can help predict next steps in drug development process.
Validation of Biological Target: (Principles of early drug discovery, 2014)
Once a biological target is identified it is further validated to ensure that the data collected because of the research has a potential to lead to a therapeutic drug development process. A range of validation studies are conducted to prove the safety and efficacy which includes but are not limited to studies on animal in vitro, modifying the biological target.
Importance of Selecting Biological Target: (Principles of early drug discovery, 2014) (Drugs and their molecular targets: anupdated overview, 2018)
To simplify, basic research introduces a biological target which after validation leads to lead discovery. A small molecule like drug showing therapeutic effects is found by intense studies and preclinical studies are conducted. Post preclinical studies the drug is further evaluated in human subjects known as clinical studies. Once the clinical studies are successful complete an NDA is filed and the drug is available for commercialization after approval from the health authorities. To conclude finding of the biological target is important in any drug development process which we can conclude to be the start of the developmental plan.
Failure to drug development process can be either because they lack efficacy or safety. Validation of the drug molecule at an early stage helps prevent the failure to development process.
Different Type of Biological Target: (Biological target, 2018)
Drugs which have been recently approved are reviewed based on the therapeutic interest and the biological target such as monoclonal antibodies, G-protein-coupled and nuclear receptors. Emerging classes include epigenetic therapy and membrane aminopeptidases which is a new receptor class. Ion channels drug target can be ligand-gated or voltage gated ion channels.
Nuclear Receptor: (Signaling by Nuclear Receptors, 2018) (Transcription factor, 2018)
Nuclear receptors belong to ligand-regulated transcription factors. Transcription factors (TFs) are proteins which binds with DNA sequence and are responsible for transferring genetic information from DNA sequence to messenger RNA. TFs function is to manage that the genes express the correct message at the correct time throughout the lifespan of a cell or organism. These TFs work together to process cell division, growth and death. RNA polymerase is an enzyme which brings about the transcription of genetic from DNA to RNA.
By acting as an activator or a repressor the TFs brings about the recruitment of the RNA polymerase. A DNA-binding domain (DBD) is present on the TF. DBD regulating the gene attaches specific sequence of DNA to the adjacent gene is a unique feature of TFs.
TFs are activated by steroid hormones and lipid soluble signals. The ligands react with nuclear receptors present inside the cell by crossing the plasma membrane. Many biological processes are processed or managed by transcription of gene. Nuclear receptor also regulates cellular functions.
Types of Nuclear receptors I, II and III: (Signaling by Nuclear Receptors, 2018) (Transcription factor, 2018)
The receptors are available as monomers, homodimers or heterodimers. These receptors recognize the Hormone response elements (HRE). HRE are DNA sequences formed by RGGTCA sequences. Based on mode of action there are four subtypes of receptors.
Type I receptor are present in cytoplasm examples include androgen receptor, estrogen receptor, and progesterone receptor. The receptor is freed from chaperone by ligand binding. This leads to homodimerization and exposure of nuclear localization sequence. Binding and activation of target genes takes place when the receptor in inside the nucleus.
Type II receptor are available in the nucleus and work in absence of ligands. Examples of Type II receptors are thyroid receptor and retinoic receptor. Type II receptors participate in cell-autonomous feedback regulation by binding with ligands available in the same cell.
The function of Type III receptor is same as Type I. The only difference is the organization of HRE.
The receptors which binds with half-site HREs as monomers are Type IV receptors.
Examples of Common Nuclear receptors and Ligands: (Signaling by Nuclear Receptors, 2018)
Few examples of receptors and ligands include but are not limited to are androgen receptor and testosterone, estrogen receptor and estrogen, glucocorticoid receptor and cortisol, retinoic acid receptor and retinoic acid, thyroid receptor and thyroid.
Estrogen Receptor: (Estrogen Receptor, 2018) (Estradiol, 2018)
Estrogen receptor are activated by estrogen hormone. There are two diverse types of Estrogen receptors nuclear estrogen receptor and membrane estrogen receptors (mERs).
Nuclear estrogen receptors are translocated into the nucleus when they are activated by the estrogen. They regulate the different gene activity. Nuclear estrogen receptor is further classified as ? and ?. These receptors are encoded on sixth and fourteenth chromosome by ER? and ER? genes respectively. Dimers are hormone activated receptors. The receptors form exists as ER??, ER?? known as homodimers and ER?? known as heterodimers.
ER? is present in endometrium, breast cancer, ovarian stromal cells, hypothalamus. The epithelium of the efferent ducts contains ER? in males.
ER? is found in ovarian granulosa, brain, heart, endothelial cells, prostrate, kidney, mucosa, lungs and bone.
Estrogen is widely used by females to treat symptoms of menopause, to prevent bone loss post menopause and in prostrate and breast cancer in both males and females.