Monday, 4 January 2016

Drugs and the Bipolar Medicinal Chemist

According to Dr Christopher J. Burns at the Walter and Eliza Hall Institute of Medical Research, a good Medicinal Chemist (MC) is a polymath. With a strong background in synthetic organic chemistry, a good MC should also have a working knowledge of the biology of their therapeutic area of interest; drug screening and biochemistry; drug metabolism and distribution; the interface between chemistry and toxicology; and intellectual property and competitive positioning.
Formerly known as both the Bipolar Economist (BE) in 2000 and Bipolar Statistician (BS) in 2004, he was reincarnated as the Bipolar Chemist (BC) in 2015. Consequently, he now possesses expertise in a number of different disciplines, namely: accounting and commercial law; economics and econometrics; biostatistics and bioinformatics; computational biology and computational chemistry; the list goes on...However, outside his scientific interests, he also LOVES music, poetry, philosophy, psychology and theology. Given his passion for both the arts and the sciences, the BE/BS/BC is a self-proclaimed polymath, and believes he has what it takes to be a good MC.

Economics and statistics of love

What makes a 'good' drug?
Drugs should meet the following requirements before being released on the market for human consumption.
  • Be potent against its target to minimise the dose required
  • Be selective over other biological processes to reduce risk of toxic side-effects
  • Display good absorption, distribution, metabolism, excretion and pharmacokinetics (ADME-PK) so that dosing is convenient
  • Possess an acceptable safety profile so that it can be dosed without undue toxicity
  • Possess acceptable physicochemistry so that the drug is stable and can be formulated
  • Be patentable so that it can be commercialised
  • Be synthetically feasible so that it can be manufactured on a large scale
Medicinal chemists are responsible for the design and discovery of drugs that meet these criteria.

Courtesy of Chemistry in Australia magazine, February 2015 (p.23)

How to discover drugs?
Drug discovery starts with identifying a biological process that can be modified to therapeutic benefit. This typically involves the inhibition of a certain function of a protein or protein complex (e.g. ion channel, receptor, enzyme) that has been shown to drive disease pathology. Once the drug target has been identified it is then necessary to find the chemical compounds that interact with the target, thereby blocking the aberrant activity associated with the disease. This is generally achieved through a process called high-throughput screening (HTS). After identifying 'hits' from HTS, the medicinal chemist's job is to modify these hit compounds to address issues of potency, selectivity and pharmacokinetics; this is done by way of drug optimisation.

What is drug optimisation?
Drug optimisation is a systems development cycle that involves design-synthesis-testing-analysis.
  • Design: At each turn in the cycle, compounds are designed to improve the desired properties while balancing potential risks from making changes to the compound. Molecular property predictions (e.g. lipophilicity, basicity, molecular weight) are used to increase the likelihood that new compounds will possess good physicochemical and ADME-PK properties.
  • Synthesis: Designed compounds are typically synthesised on milligram scale for initial testing. Compounds must also be synthesised in a robust and efficient manner to ensure that analogues can be easily prepared.
  • Testing: Preliminary screens will test potency and selectivity in biochemical and cellular assays. Further study is then undertaken via a screening funnel (as shown below).
  • Analysis: Data for a suite of compounds from the assays undertaken is analysed to determine the effect of each individual chemical modification on the overall activity profile of the drug.

Courtesy of Chemistry in Australia magazine, February 2015 (p.24)

Compounds that successfully make it through the funnel can then undergo more elaborate preclinical profiling, which may include broader toxicity assessment, human material studies and process chemistry development (Burns, 2015). 

What drugs are the Bipolar Chemist interested in studying?
Apart from Bipolar Disorder, the Bipolar Chemist is also afflicted with two other chronic illnesses, namely Hypertension and Haemochromatosis. A list of his medications and treatments are given below.

Bipolar Disorder 
  • Epilim (sodium valproate) - mood stabiliser 
  • Seroquel (quetiapine) - atypical antipsychotic 
  • Lexapro (escitalopram) - selective serotonin reuptake inhibitor (SSRI) 

  • Coversyl Plus (perindopril erbumine/ indapamide hemihydrate) - angiotensin converting enzyme (ACE) inhibitor / chlorosulphamoyl diuretic  
  • Deferoxamine (chelating agent used to remove excess iron from the body)

Previous medications include Lithicarb (lithium) and Saphris (asenapine). His psychiatrist has also considered prescribing him with Lamictal (lamotrigine) and N-acetylcysteine (NAC) as adjunctive therapies.

Is it safe to combine these drugs?
Certain combinations of medicines (prescription or otherwise) cause side effects that do not arise when individual substances are taken alone. Studies published over the past two decades suggest that such  "drug interactions" cause more than 30 percent of side effects from medications (Wapner, 2015). Unfortunately, pharmaceutical companies cannot always predict when a new drug will mix badly with other medicines - not to mention supplements or foods - and so unexpected deaths are sometimes the first warning sign. In response to this "deadly drug combination" problem, new software and gene analysis tools are being developed to predict which medicines can become harmful when taken together. Bodies like the Precision Medicine Initiative (a project led by the National Institute of Health) and Center for Drug Evaluation and Research (at the Food and Drug Authority) are developing the following:
  • A national databank that facilitates genetic testing and analysis by local pharmacists to identify key genetic variants that affect our body's ability to process different drugs;
  • Computer models that use clinical research data to calculate how one drug will alter the concentration of another when both drugs are metabolised by the same enzyme
The aim of these initiatives is to give patients clearer warnings on drug labels about possible drug interactions and easy-to-understand recommendations on how a dose should be altered (based on computer modelling) when additional drugs are introduced.

"N-of-1 medicine
Rather than trying to design drugs that fit best for a whole population, the Bipolar Chemist's vision is to create his own personalised treatment to combat his illnesses in isolation. Only time will tell whether this polymath can deliver on this promise. 

Burns, Christopher J. (2015) Medicinal Chemistry: Central to Drug Discovery, Chemistry in Australia, Feb 2015, 22-25
Wapner, Jessica (2015) Deadly Drug Combinations, Scientific American313, 29-30