I had a conversation last night with the second in charge in a major New York based drug design company. The company is heavily involved in the design and development of new anti-cancer drugs. The technical part of our conversation wasn’t as long as I’d have liked, but we did cover a few topics.
- Lock and key molecular simulations. How molecular modelling works for fitting a small molecule into a protein.
I asked about the optimisation technique used for doing this. J explained. One problem is that molecules are flexible, both the protein and the small molecule. Taking all the possible rotations of parts of the small molecule into account one builds up a map of static charge. Ditto for the active site on the protein. Here there’s an art to modeling enough of the protein to allow sufficient deflection of the active site, but no so much that the protein configuration gets excessively floppy.
In each case we’re most interested in the comparison of a new small molecule to an existing one. The aim is to find a new molecule that fits better into the active site than the existing one, or at least as well. So we start with the existing molecule and program a transitional map of static charge that morphs one small molecule into another. This gets run in computer simulation over an equivalent real time of a few milliseconds, in the presence of water. If the result doesn’t work, run it at a finer timescale over a few more milliseconds.
We both agreed that Hartree-Fock, itself a simplification of the real quantum mechanics equations, can’t be used because it would take far too long.
- Benzene molecular simulation.
I commented that when I did a molecular simulation of benzene, it came out non-flat. J explained that there is a technique for forcing it flat, and J agreed. J followed on and said that you know your molecular simulation is wrong if there’s a bond passing through the centre of a benzene molecule. It can happen, and happens in the simulation because the simulation program doesn’t know that if you stretch the bonds of a benzene molecule too far, it breaks.
- Covid was the fastest vaccine approval (vs slowest vaccine approval).
J said that vaccine approval for covid was the fastest ever. And he said that he heard that from someone he trusts. I said that I thought it was the slowest ever, but that was not based on information from someone I trusted. What J said has to be trusted but can’t be correct in general, because it’s not true for smallpox, polio, or the hundred or so flu vaccines.
So I need to investigate approval times for other vaccines that are used. Can’t include vaccines that never got manufactured (even if they did get approval). Which vaccines, if any, took a longer time to approve than Covid vaccines, nine months?
I commented that the Chinese had vaccinated 1.5 million people before America approved any vaccine. J agreed, and said that the United Arab Emirates using Sinovac had early vaccinations as well. But he said that the Sinovac vaccine has low effectiveness. I commented that Russia had vaccinated 100 thousand people before America approved any vaccine, and he agreed to that, too. I added that the Chinese approval was for “emergency use only” and J said that all vaccines should be like that. I agree.
J also said that the Covid anti-viral was approved in record time. I have no reason to doubt that.
- Testing on rats then either dogs or monkeys, before humans.
J said that testing was always done first on rats, then on either dogs or monkeys, before being tested on humans. (My opinions on this were not discussed).
- MDCK dog kidney cells.
I mentioned dog kidney cells, and asked why they were used. J said that they do use MDCK cells. They are very useful for permeability studies, whether the drug passes through a layer of cells. J said that they were used simply because they were an immortal cell line, not because being kidney cells had any particular relevance.
- Only 10% of drugs submitted to the FDA get approval.
J said that it costs about a billion dollars, or more, to get FDA approval. J said that only 10% of the drugs submitted to the FDA successfully pass through the approvial process. I’m sure that I’ve seen statistics that the approval rating is a lot higher than that, but didn’t say so. Perhaps the approval rating has dropped since the statistics I saw, or perhaps he’s thinking of anti-cancer drugs. No Covid vaccine submitted was rejected, only one was withdrawn by the developers, the Australian vaccine because it could lead to false positive results on AIDS tests, not because of ineffectiveness.
- Malaria vaccine.
I asked about the malaria vaccine. J said that was a difficult one, but it was very near final approval. I replied that it was very near final approval four years ago, which he agreed was possible. He said he’ll check it up.
- Stage 4 drug testing.
I had made a mistake, a big one, I think. I couldn’t find anything on Google Scholar about the history of the phases of drug testing required for approval. I realise now that that was probably because I should have been looking up “stages” not “phases”. I’ll have to go back and look again.
Stage 4 drug testing is the evaluation after the drug is manufactured and circulated. I hadn’t known that. J says that many drugs now go through Stage 4 evaluation, and that quite a few are withdrawn because of it.
- Covid vaccine keeps people out of hospital.
We were talking about how Covid vaccine doesn’t hinder transmission, but does keep people out of hospital. I commented, I think now incorrectly, that either that or more recent strains are milder. J didn’t agree and said that countries with lower vaccination rates have more people in hospital. I waffled on about Africa. But I think now that I’ve already proved that vaccination lowers the death rate.
- J catching Covid.
J himself had had three doses of vaccine before catching the virus. During the Omega wave, they decided to go to the Museum of Modern Art, MOMA. Everyone there in order to gain entry was vaccinated, masked and temperature checked. They were only there for half an hour. One of his kids tested positive two days later and the other one the next day. J and his wife didn’t catch it from the kids. J thought “we’re over it now”.
After the main Omega wave had passed, J and his wife decided it was safe enough and went to a nightclub. Both caught Covid there. And passed it on to the kids.
- Covid effect on children vs adults.
J was sick for four weeks, couldn’t get out of bed for one week. Fever and coughing and breathing difficulties. I pointed out that Covid was first identified as a pneumonia cluster, he hadn’t known that.
J’s children only had very mild symptoms, his youngest with just the sniffles, his older (year 10 at school) had more serious symptoms but was over it in a week.
J’s mum also caught Covid, completely independently. She has had breathing difficulties for many decades of unknown cause so was quite worried. But this time after the anti-viral was available, and she got over it fairly easily.
- Hydroxychloroquine.
I commented that China had given this drug to Covid patients even before Covid was known to exist, back in December 2019. I lied. The Chinese used chloroquine back then, and only switched to hydroxychloroquine in January 2020. J speculated that hydroxychloroquine may have killed someone that he knew. The person had breathing difficulties, and hydroxychloroquine is known to have side effects. “We’ll never know”, he said.
- Four endemic strains of coronavirus.
We agreed that SARS is a coronavirus. I commented that I had known about coronavirus from reading that a significant fraction of the common cold was caused by a coronavirus. J replied that there are four endemic strains of coronavirus that have been around for a long time. I hadn’t known that.
- Cancer and Oncogenes.
J’s company’s main work is in finding anti-cancer drugs. And they’ve has success with a type of bone marrow cancer, myelo-somethingorother. Anti cancer drugs these days is about finding multiple layers of treatment. A first treatment is used, and if the cancer grows resistant to that then a second treatment, and so on. Most cancers these days have four levels of treatment, in some cases five levels of treatment.
I didn’t say that I’ve found the same about headaches, as each type of headache tablet becomes inneffective, switch to a second, then a third, then a fourth.
I commented that there seem to be an almost infinite number of oncogenes. He didn’t agree but said “There are a lot, I’ll grant you that”. Blocking oncogenes would be his bread and butter.