Drug discovery pathway and challenges involved in the process

What is Drug Discovery?

A drug is any chemical that has therapeutic effects on the recipient. And Drug Discovery is a process by which new drugs are invented and brought to medical practice. A wide variety of strategies are adopted by the pharmaceutical industry to identify new drug products. New drugs are discovered either by serendipity or by applying various experimentation and optimization techniques.

Drug discovery in the past often resulted from serendipitous observations of the effects of plant extracts or individual chemicals on animals or humans. The present-day approach relies more on high-throughput screening of libraries containing hundreds of thousands or even millions of compounds to their whether they can interact with a specific molecular target or elicit a specific biological response. 

The whole process of drug discovery involves: [1]

• screening of a wide range of biological materials to knowledge-based drug design
• Then in preclinical trials, potential candidates are subjected to a range of in-vivo and in-vitro tests to know their safety and efficacy in treating their target disease.
• Then after taking the approval of concerned government agencies clinical trials are conducted on citizens in different phases.
• After the clinical trials, a huge amount of data is generated which is shown to the government authorities.
• Based on generated data a drug may be allowed for production
• Post-marketing surveillance is generally undertaken, to know any subsequent drug-induced side effects/adverse reactions.

Small vs Large Molecules

So drug discovery is a huge process that takes a lot of time and money and also the probability of developing a Nobel drug is very less than its failure. But the advancements in computational biology have accelerated the drug development process.

Before going into this discussion let’s discuss Lipinski's rule of five which is considered a thumb rule to evaluate drug-likeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it likely orally active drug in humans. 

• No more than 5 hydrogen bond donors
• No more than 10 hydrogen bond acceptors 
• A molecular mass of fewer than 500 daltons.
• An octanol-water partition coefficient (log P) that does not exceed 5

Omeprazole is a popular drug that conforms to Lipinski's rule of five 

Computational Approach to the drug discovery process

We have developed databases containing detailed chemical information about millions of chemicals and detailed structural information about many human proteins.

The computational approach is to “roll” all the chemicals over the protein of interest to find those with high-affinity interactions. [1]

The size of the databases is increasing at a tremendous rate. One day we may have almost all the protein sequences and their structures available in these databases. The idea is to discard thousands of compounds that have unwanted or no interaction with the drug to fasten the drug discovery process. Finally, we also will want to predict the structural and functional consequences of a drug binding to its target, as well as all relevant pharmacokinetic properties of the molecules of interest to some extent. It is also true that computational evidence must be supported by the wet laboratory results.

BIOPHARMACEUTICALS

Any pharmaceutical drug product which is manufactured in, extracted from, or semi-synthesized from any biological source is called biopharmaceutical.

Researchers have identified a wide variety of proteins produced naturally in the body which have obvious therapeutic applications. Examples include the interferons, and interleukins, which regulate the immune response; growth factors such as erythropoietin, which stimulates red blood cell production; and neurotrophic factors, which regulate the development and maintenance of neural tissue. 

Recombinant DNA technology has had a four-fold positive impact on the production of pharmaceutically important proteins:

• It overcomes the problem of source availability
• It overcomes problems of product safety
• It provides an alternative to direct extraction from inappropriate/dangerous source material
• It facilitates the generation of engineered therapeutic proteins displaying some clinical advantage over the native protein products.[2]

Step-1 Basic research (synthesis, examination and screening)

At this stage of the process, thousands of compounds might be potential candidates but after early testing, only a small number of compounds look promising and move forward in the process.

Screening of drug molecules is done from a library of hundreds/thousands of molecules that have the ability to interact with specific molecular targets or elicit a specific biological response.

High Throughput Screening 

High throughput screening (HTS) is the use of automated equipment to rapidly test thousands to millions of samples for biological activity at the model organism, cellular, pathway, or molecular level.

HTS assays are performed in microtiter plates in 96-, 384-, or 1536-well formats while traditional HTS usually tests each compound in a compound library at a single concentration, most commonly 10 μM.

HTS approaches are now being utilized more and more to facilitate ADMET/DMPK (absorption, distribution, metabolism, excretion, toxicity/drug metabolism and pharmacokinetics) activities.

One of the advantages of HTS is that it works even when the structure information of a target protein is not available.

The limitations include the low hit rate due to incompatible libraries and the potential false positives, which need to be eliminated. [3]

The best thing about HTS is a wide range of ligands namely receptors, enzymes, ion channels or other pharmacological targets can be screened.

Step-2 Pre-clinical research [4]

In the drug development process, preclinical testing occurs before clinical trials. It is done on cells, components of cells, organs and laboratory animals to check for drug efficacy, toxicity and selectivity. Preliminary data related to all the tests are also recorded. 

Regulatory authority approval to commence clinical trials is based largely upon pre-clinical pharmacological and toxicological assessment of the potential new drug in animals. Preclinical studies generally, can take up to 3 years to complete and at a cost of anywhere between $10 million and $30 million. On average, approximately 10% of potential new drugs survive preclinical trials.

Guidelines are usually provided by the regulatory authorities for pre-clinical studies.

Isogenic-Human disease models and Stem cell disease models are used to conduct. [2]

In-Vitro

Basically in-vitro means test-tube experiments. Studies are done on cells, sub-cellular components or subcellular extracts or purified molecules.

In the last several years the in-vitro testing model has served as the primary testing model for cancer drugs. While it does help bring new drugs to clinical trials faster and with less cost, it doesn’t give the best picture of how a patient will react to the drug.

Isogenic-Human disease models and Stem cell disease models are used to conduct in-vitro studies. Isogenic human disease models are a family of cells that are selected or engineered to accurately model the genetics of a specific patient population, in vitro.

Embryonic stem cells carrying or induced to carry defective genes can be investigated in vitro to understand latent molecular mechanisms and disease characteristics

In-Vivo

In In-vivo studies, tests are performed on live organisms. Generally, in-vivo studies are carried out to get information about the metabolic profile, toxicology, and pharmacokinetics of the drug.

In order to assess the safety of the drug, various studies are carried out in animals such as mice, and rats under varying conditions of drug administration. 

The important tests include: 

• Systemic toxicity studies 

1. with a single dose - done to determine the minimum lethal dose and maximum tolerated dose
2. with repeated doses - final systemic toxicity studies are carried out

• Local toxicity studies:- Drug is applied to local sites like skin or vagina etc.
• Specialized toxicity studies:-

1. including tests for male fertility 
2. female reproduction and fetal developmental toxicity
3. allergenicity/hypersensitivity
4. genotoxicity and carcinogenicity

Studies on animals would only indicate probable beneficial and toxic effects that may be expected during human trials. But it can never give an absolute idea about the efficacy and safety of the new drug on humans. 

It is known that the pharmacokinetics and pharmacodynamics of a drug differ both qualitatively and quantitatively in different species. A drug found highly effective in animals may be totally ineffective in humans because of differences in genomic profiles

Clinical Trials

It involves the study of various aspects of pharmacodynamics and pharmacokinetics in humans, both in health and in disease.

→ Phase 0 studies were recently recommended by US FDA for some drugs.

→ Every patient in a phase III study is watched closely. The study will be stopped early if the side effects of the new drug are too severe or if one group has much better results. [5]

After the completion of the clinical trial, the results are subjected to statistical analysis. But Statistical significance and Therapeutic significance of results are not necessarily equivalent.

Challenges Involved In The Process

• The drug development process is a lengthy, complex and costly process. And chances that the drug will succeed are very less.
• Animal models often cannot recapitulate an entire disorder or disease. So the inability of animal models to accurately predict efficacy as a challenge to drug development is also a major problem.
• Identification of biomarkers is also a major problem. According to Fleming and Powers, biomarkers are indirect measures of clinically meaningful endpoints, which are direct measurements of how patients feel, function, and survive. [6] 
• For drugs having receptors in the brain, one prominent challenge is that mechanisms behind nervous system disorders are poorly understood.
• Failed clinical trials are almost predictable simply due to patient heterogeneity. When planning clinical trials, it will be important to consider patient groups in which the mechanism of disease is most likely to be homogeneous. Patient stratification could produce better clinical trial outcomes and additional information about potential therapeutic targets. [7]
• Reproducibility remains a critical issue for translation. The ability to rely on published data and process those data from one lab to another is critical for the successful translation of discovery research. [7]
• Inadequate Collaboration among Academia, Industry, and Government. The greatest challenge is that the majority of the field is working competitively on the same few molecular targets. [8]

Conclusion

During the past 15 years, companies have steadily increased expenditures on research, but the number of new drug approvals has dropped due to the above-mentioned challenges which companies face during the drug development process. New drugs are discovered either by serendipity or by applying various experimentation and optimization techniques. This decade focused much on drug repurposing. The advancement in bioinformatics and the vast amount of data we have accelerated the process. Very high investments are not required for drug repurposing. Most part of the work is done by computers. Even for SARS COV-2, we got many drugs within 6 months as all were repurposed drugs. Reverse pharmacology is also gaining importance these days. The integration of machine learning and AI is another popular and new approach in the drug discovery pathway. So it is true that we have come this far but there is a lot to come.

by Anant Kumar

References

[Imagelink]https://en.wikipedia.org/wiki/Lipinski%27s_rule_of_five#:~:text=Lipinski's%20rule%20of%20five%2C%20also,it%20a%20likely%20orally%20active

[1][THE_PHARMACOLOGICAL_BASIS_OF_THERAPEUTIC, CHAPTER_1,GENERAL PHARMACOLOGY]

[2][biopharmaceuticals-biochemistry-and-biotechnology-walsh-wile, c_1, page_8]

[3]M.S. Attene-Ramos, ... M. Xia, in Encyclopedia of Toxicology (Third Edition), 2014 HTS can also be applied to reveal inducible pockets in protein-protein interfaces, as well as allosteric modulators.16 (Doubt..ask sir)

[4][https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research]

[5]https://www.nccn.org/patients/resources/clinical_trials/phases.aspx

[6]Temple RJ. In Clinical Measurement in Drug Evaluation. Nimmo WS, Tucker GT, editors. New York: John Wiley; 1995. p. 790. (A regulatory authority’s opinion about surrogate endpoints).

[7]IOM. Improving the utility and translation of animal models for nervous system disorders: Workshop summary. Washington, DC: The National Academies Press; 2013.

[8]Forum on Neuroscience and Nervous System Disorders; Board on Health Sciences Policy; Institute of Medicine. Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary. Washington (DC): National Academies Press (US); 2014 Feb 6. 2, Drug Development Challenges. Available from: https://www.ncbi.nlm.nih.gov/books/NBK195047/