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Chemistry and the Discovery of New Medicines

By zccasle, on 11 February 2015

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CPS Talk 2.2.15 Dr Dave Alker, Phzer

Dave Alker, Medicinal Chemist and Recruitment Manager at Phzer spent the first 5 minutes of his talk insisting that everyone who studies chemistry is great. Thanks Dave. Perhaps he was worried that university chemistry departments are populated by modest and uncertain shrinking violets… He told us that we already know more about chemistry than Harry Kane or Zoella and hence we are on the road to becoming experts. Dave was fired up on coffee and general gumption for chemistry. If anyone in the room had felt meandering upon entry, I think they would feel less meandering on their way out.

A seasoned medicinal chemist, Dave had started working at Phzer in the eighties around about the time of the HIV-AIDS scare. He has a rather fascinating incite into how a pharmaceutical company attempts to deal with such a scenario.

Ordinarily, in the absence of a health scare, a pharmaceutical company will operate under three motivations; can an existing therapy be improved? Is the scale and impact big enough to warrant the investment? Is there a sufficient theoretical starting point; has a target been defined?

‘The Target’ is a key feature of the development of a therapy. It is the medicinal equivalent of pre-crime, unless the target has been defined therapies are constrained to treat symptoms. Hence it is the root mechanism of an ailment. For example the adrenergic receptors where the targets for beta blockers and a whole host of other drugs. Finding the target is a massive component of biochemical research. For example, the underlying cause of Multiple Sclerosis is not accurately known and hence it cannot be treated directly.

HIV-AIDS during the eighties was a profoundly frightening thing, with what appeared to be a 100% mortality rate. In the event of such publicised health scares, pharmaceutical companies have even been known to collaborate so that progress can be made more quickly. Such is the potency of the virus that no cure or vaccine currently exists, only a therapy that is able to keep the virus at bay and prevent or delay the onset of AIDS.

One might expect that the target for a viral infection should be the virus itself, this has however been found to be impossible to implement given the fast mutation of the virus. So in the case of HIV the best therapy presently relies on refusing HIV entry into the T4 cells. This radically hinders their propagation.

Development of this method required in depth knowledge of the viral mechanism so that it could be inhibited. It required the isolation of a specific protein on the surface of a white blood cell called CCR5. The viral mechanism involves binding to CCR5 after which it becomes incorporated into the T4 cell, which it destroys. Thus the target was the CCR5 receptor protein, if it could be blocked to HIV then the entire viral spread could be stopped. This is where the medicinal chemistry begins.

Maybe I made a mistake when I was writing this down, but Phzer tested 0.5 million compounds against CCR5!? This is to provide ‘the lead’, the molecule that has the right general applicability in terms of lipophilicity, potency and ligand efficiency. After the lead, the task begins to improve the action of the molecule. This can be related to how the molecule behaves in the body, can it gross the gut wall, does it impede ion channels, does it become oxidised by the liver and get excreted too quickly? All of these problems occurred during the development at Phzer but thanks to the chemists who are able to manipulate the structure and functionality of molecules, they arrived at a therapy; Maraviroc. It was gradually tailored so that the addition of functional groups or structural elements gave it the desired action inside the body. Dave assures us that its synthesis should contain nothing alien to a Chemistry undergraduate, insisting that it’s discovery was dependent on thorough and systematic practices as opposed to strokes of genius.

Often the challenge does not end there, it still requires a chemical engineering treatment so that it can be synthesised in vast quantities. In addition, the stability and administration of the compound need also be considered. In the end it was education the stemmed the spread of HIV and prevention is consistently the best defence.

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