{"id":24410,"date":"2021-11-13T16:41:01","date_gmt":"2021-11-13T16:41:01","guid":{"rendered":"https:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=24410"},"modified":"2021-11-13T16:41:01","modified_gmt":"2021-11-13T16:41:01","slug":"first-came-molnupiravir-now-there-is-paxlovid-as-a-sars-cov-2-protease-inhibitor","status":"publish","type":"post","link":"https:\/\/rzepa.net\/blog\/2021\/11\/13\/first-came-molnupiravir-now-there-is-paxlovid-as-a-sars-cov-2-protease-inhibitor\/","title":{"rendered":"First came Molnupiravir – now there is Paxlovid as a SARS-CoV-2 protease inhibitor. An NCI analysis of the ligand."},"content":{"rendered":"

Earlier this year, Molnupiravir<\/a> hit the headlines as a promising antiviral drug. This is now followed by Paxlovid<\/a>, which is the first small molecule to be aimed by design at the SAR-CoV-2 protein and which is reported as reducing greatly the risk of hospitalization or death when given within three days of symptoms appearing in high risk patients.<\/p>\n

\"\"<\/a><\/p>\n

The Wikipedia page (first created in 2021) will display a pretty good JSmol 3D model<\/a> of this; the coordinates being generated automatically on the fly from a SMILES string, which specifies only what atoms are connected in the structure by bonds.\u00a0Given that the structure of this molecule as embedded in the SARS-CoV-2 main protease[cite]10.1007\/s13238-021-00883-2[\/cite] has been determined (and can be viewed here<\/a>),\u00a0I thought I might display those coordinates as an alternative to the Wikipedia\/JSmol generated structure.<\/p>\n

\"\"
Click to get 3D model<\/figcaption><\/figure>\n

I extracted the ligand from the PDF file and then added hydrogens manually to obtain the above result.‡<\/sup> There are two noteworthy points about these representations:<\/p>\n

    \n
  1. A mystery concerns the nominal C\u2261N group on the top right, which displays an angle at the carbon of 117\u00b0. A cyano group is of course linear (180\u00b0). This is not a defect of the crystal structure determination, but an indication of a rather stronger interaction occurring (as indeed noted[cite]10.1007\/s13238-021-00883-2[\/cite]). The distance between the carbon of the cyano group and an adjacent sulfur is 1.814Å, which indicates a covalent bond has formed to the cyano group. The nitrogen of the erstwhile cyano group is 3.013Å away from an adjacent NH group, which suggests it is stabilised by a hydrogen bond.<\/li>\n
  2. Crystal structure searching of units with S…C…N in which the N has only one bond reveals zero hits, but searches of S…C…NH reveal nine hits, with S…C distances in the range 1.74 – 1.80Å and C…N distances in the region 1.25-1.27&Aring. The reported CN distance is 1.251&ARing, confirming that when bound to the protein, the cyano group is replaced by an S-C=NH group and hence is clearly an important component of the mode of action of Paxlovid.
    \n    \"\"<\/a>\n\t<\/li>\n
  3. The conformation of Paxlovid is in one respect not fully represented by the\u00a0Wikipedia diagram<\/a>, as shown below. This implies the t-butyl<\/strong> group (on the left) as being well separated from the pyrrolidinone<\/strong> ring system at the right of the molecule.
    \n\"\"
    \nIn fact the two groups are adjacent, being held in that conformation by probably a combination of weak dispersion forces and a contribution from the surrounding protein in the crystal structure. This is more graphically shown by the NCI (non-covalent-interaction) diagram below (DOI:     10.14469\/hpc\/9964<\/a>), where the green areas in the region between the two groups (ringed in red) represent stabilising interactions between them. You might also spot other green\/cyan regions indicating additional weak hydrogen bonds between C-H groups and oxygen!<\/li>\n<\/ol>\n
    \"\"
    PAXLOVID NCI analysis<\/figcaption><\/figure>\n

    There are only a small number of crystal structures of small molecules containing the S-C=NH motif. I will try to find out how common this is in protein-ligand structures.<\/p>\n

    \n

    ‡<\/sup> There are many tools for performing this operation. I used the following procedure. I downloaded the PDB file (https:\/\/files.rcsb.org\/download\/7vh8.cif<\/a>), opened it in CSD Mercury, selected the ligand (by identifying the CF3<\/sub> group and clicking on one atom), inverted the selection so that everything but the ligand was then selected and using edit\/structure, I deleted the selected atoms, leaving only the ligand.<\/p>\n

    Postsript<\/h2>\n

    The cyanopyrrolidine group such as in Paxlovid is well known as a specific probe.[cite]10.1039\/D1MD00218J[\/cite],[cite]10.1021\/jacs.0c04527[\/cite],[cite]10.1021\/acschembio.0c00031[\/cite] CovalentInDB is a comprehensive database facilitating the discovery of such covalent inhibitors[cite]10.1093\/nar\/gkaa876[\/cite] and is available here<\/a>. There is also a program called DataWarrior<\/a> that is potentially able to find such probes.<\/p>\n","protected":false},"excerpt":{"rendered":"

    Earlier this year, Molnupiravir hit the headlines as a promising antiviral drug. This is now followed by Paxlovid, which is the first small molecule to be aimed by design at the SAR-CoV-2 protein and which is reported as reducing greatly the risk of hospitalization or death when given within three days of symptoms appearing in […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,6,8,11],"tags":[],"class_list":["post-24410","post","type-post","status-publish","format-standard","hentry","category-chemical-it","category-crystal_structure_mining","category-general","category-interesting-chemistry"],"_links":{"self":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts\/24410","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/comments?post=24410"}],"version-history":[{"count":0,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts\/24410\/revisions"}],"wp:attachment":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/media?parent=24410"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/categories?post=24410"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/tags?post=24410"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}