In this video we discuss Raloxifene, an FDA-approved drug which was recently found by Europe’s Exscalate4CoV to be a potential inhibitor of SARS-CoV-2 replication.
Hey everyone for our covet 19 nvr series we’re going to be exploring some of the drugs that escalate for cove has been using super computers and nano to find drugs that they could repurpose to help fight covid19 what we see here is raloxophene which is you know one of the drugs that the consortium has found that actually shows some pretty good potency experimentally
And computationally that it could potentially inhibit covid19 so we’re going to be going through some of the papers that are out there related to this molecule uh related to some of the proteins that we’ve already been exploring as well as some new proteins that are out there with the vitamins and as well and before we jump in steve why don’t we take a look at
This molecule this reloxapine so this this molecule is a selective estrogen receptor modulator so in the body it binds normally to the estrogen receptor but unlike natural estrogens such as estradiol this one can be both an agonist and some issues or an antagonist in other tissues so in bone it’s an agonist and help build bone and protects against osteoporosis
So it’s given to post-menopausal women whose estradiol levels are lower but it’s also been found in the breast and uterus it can block the function of estradiol and so it’s used to treat breast cancer as well so it’s a really fascinating drug i saw that in 2017 in the u.s alone there were 900 000 prescriptions for aloxtophene it’s now a generic medicine steve
Inexpensive medicine for people so if it does work for cobia 19 it would be a great breakthrough and and mike there’s been some um i i guess uh you know information out there saying that maybe men are more affected uh you know bicovit 19 than women are and so this is very interesting that there is this you know estrogen receptor modulator um that we’re looking
At that could potentially be related to kevin 19 so um yeah it’s going to be interesting to check this out as a potential treatment i don’t know what the side effects would be for men and women both taking this uh they wouldn’t typically be in the age range or group that would normally be taking this type of medicine um but if it helps fight covenanting like you
Said it’s generic drug it’s generally available it’s pretty cheap so if it ends up you know helping fight kevin 19 and actually attacking the virus server um yeah that would be awesome so let’s go ahead and explore a little bit about what’s going on in the research and see if we can make sense of how this interacts with the chronovirus and you make a great point
Stephen it’s actually been tested in men for multiple months for osteoporosis and also looking at effects on gynecomastia so where men for instance grow breast tissue and so this could possibly help for that it’s not approved for those indications in men and more studies would be needed but there is the question of you know maybe it would be state i think for
People with covet 19 who have various cardiovascular or blood side effects this could also be a risk potentially so again there’s important research that would need to be done but yeah let’s let’s look at it and see for cobia 19 it’s not thought that it worked through binding to the estrogen receptor but that it actually could bind the proteins of the coronavirus
Oh and you know like all the papers that are out there don’t try this at home um you know if a doctor ends up describing this to you that could be interesting uh it’s going to be up to their judgment depending on your medical conditions and what medication you might already be taking but let’s go ahead and explore how this might help and yeah maybe uh we’ll end
Up seeing this prescribed in the hospitals or at least in the clinic in some time in the near future yeah so so there’s a couple papers out there that hypothesize how this might be working for covid19 and we can talk about a couple of them and one is a paper that came out recently by duarte and co-workers from cornell wheel and king’s college and they suggest
Through their docking that this could be an inhibitor of both the rna polymerase protein or the main protease protein that it could be either or both so why don’t we start with one of those steve yeah yeah sounds great so uh this is going to be a familiar protein to our audience over here so this is actually the main protease we’ve looked at it before um yeah
There’s been several different ligands found in this you know active region of the protease um yeah we’ve seen more ligand-like molecules we’ve seen artificial intelligent generated molecules based on the scaffolding techniques those sound great but one of the problems with new drugs is that it takes a while to understand if it’s going to harm people more than
It helps people but the cool thing about reluctant is that it’s already on the market and we know that it you know it is safe enough to take for people so if there is any indication that it does interact with yeah this protease over here and you know you could show that computationally a little bit like in the studies um yeah this could be a really promising
Medication there because it already is available doesn’t hurt people and it could be available for pretty cheap yeah so that’s really exciting steve and i think uh you know it was found through a docking procedure or or it was shown through a docking procedure to suggest it could inhibit this protein so maybe we should do some docking too yeah um so i uh just
Ran the docking and so we could see that in the uh the docking menu so yeah we could see the the lowest confirmation here of negative 6.9 kilocal per mole and this is actually on the original molecule that was in here on the crystallized protein ligand conformation uh this isn’t the loxaphene so the lowest energy state for reloxifen is going to be this one which
In all the others we see that this part is actually sticking into the protein and that actually generates a lower energy therefore better uh binding fit and in this way it has yeah this side sticking in which doesn’t really make as much sense as some of the other conformations that had uh that other part in there so if we look at uh the highest energy it’s going
To be the opposite there where we see that we have this part actually in the binding spot and then we have the area with the nitrogen actually sticking out and these are going to be the top view so this is negative 9.1 kilocal per mole this is our number two spot uh negative 8.6 and really the only difference is that this is just flipped up or down and chances
Are it’s going to be you know sort of moving anyways and that these are both probably pretty valid states that it would be in steve if you go back to the best one the the lowest energy confirmation of minus 9.1 yep we can we can see some hydrogen bonds that are possible from the phenol up here and the phenol down here that you know could be very good interactions
And then through the the middle of the structure where the protein is more hydrophobic uh this hydrophobic part of raloxane fits very well so from an old tip to phenol tip it’s a really good fit yeah yeah that’s a it’s a really interesting fit that it has and that yeah this part kind of sticking out of the pocket might even push away the dimer interface um
We’ll have to look to see that so yeah do you want to move on and uh check out some of the other proteins that relocate might also interact with yeah that sounds great yeah um so this is another protein that we’ve analyzed on our code nvr series before it’s the rna polymerase and so this uh rna polymerase is actually showing another drug that we’ve covered with
Remdezavir and so what remdezavir does is it’s an rna analog so it’s very similar to an rna based pair and it will actually bind with the rest of the rna sequence here and really block replication of the viral rna yeah so it’s a really cool inhibitor and i think it’s interesting that in the paper by duarte and co-workers they find that prolocifin may be a good
Inhibitor of the rna polymerase i think the question for us steve is where might it bind rna polymerase yeah so i i think that um you know figuring out which part of the polymerase it binds to um is gonna probably require a bit more processing time so maybe we’ll do a follow-up on that and do a instead of a site-specific binding uh you a virtual docking we’ll
Go ahead and do a non-site susp specific so instead of specifying that we only want it to look here we’ll actually have it go across the entire protein and find a spot where it binds because it might be some allosteric interaction where it binds on a different part of the protein that ends up changing some of the activity so thanks everyone for checking out this
Kobe 19 nvr series on reluxathene uh stay tuned we’re going to be researching the latest papers and really trying to present this information in a way that makes sense using virtual reality and mike yeah thanks so much for joining again and you’re lending your expert knowledge on medicinal chemistry thanks steve it was fun today thanks everyone cool thanks a lot everyone
Transcribed from video
COVID-19 in VR: Repurposing Raloxifene By Nanome
