-
New GPCR structures: SMO, 5-HT1B, 5-HT2B
Since the last GPCR structure post of jpo, three novel GPCR receptors have had their structure solved.
1) 5-hydroxytryptamine receptor 1B, 5-HT1B, in complex with the agonist Ergotamine(4iaq) (1)
2) 5-hydroxytryptamine receptor 1B, 5-HT2B, in complex with Dihydroergotamine and Ergotamine (4ib4, 4iar) (1)
3) The first class F receptor, the Smoothed Homolog (2), in complex with an agonizing anti-tumor agent, LY2940680 (4jkv)
The latter gave me quite a headache since its sequence identify with class A GPCRs is <10, and it is missing some of the very conserved motifs. Trying to align it with pure sequence alignment is next to impossible. Luckely I could make use of 3D-Coffee, heavily overweighting the pairwise structural alignment produced by TMalign and sap. Mind you, the alignment could probably be optimized manually, but it is quite encouraging to see an automated mechanism doing such a good job. Oh, did I mention, you'll be able to inspect all of these alignments yourself in the upcoming version of the GPCR SARfari?
1. 4iaq (red) - Human 5-hydroxytryptamine receptor 1B
2. 4ib4A (red) - Human 5-hydroxytryptamine receptor 2B
3. 4jkvA (orange) - Human Smoothened Homolog
4. 3vw7 (pink) - Human Proteinase-activated receptor 1
5. 1f88A (yellow) - Bos taurus Rhodopsin
6. 2rh1 (green) - Human Beta-2 adrenergic receptor
7. 4djhA (violet) - Human Kappa-type opioid receptor
8. 4ej4 (blue) - Mus musculus Delta-type opioid receptor
Despite being so structurally different, there is a good conservation in the 3D structure - See figure 1. The superimposing was done using mnyfit, a program jpo wrote (3) sometime back when he was still a young lad pursuing a PhD degree. Oh, and a(nother) small teaser, that screenshot comes from the updated version of the GPCR SARfari I'm working on, where you can interact with the superimposed structures, showing ligands, binding sites etc.
It seems the next major one will be the first class B, the Glucagon receptor. Hopefully this won't break my code and set back my work a few weeks.
10 20 30 40 50 4iaq ( 38 ) y-iyQdsislpwkvllvmllal-i 4lb4A ( 48 ) ee-q-gnkl-hwAallilmv 4jkvA ( 190 ) sgqÇevPLvrTdnpkSwyedveGÇGI-qçqNpLFteaeHqdMhsyIaa-f 3vw7 ( 91 ) dasgYLtsswLtlfVPsvYtg-V 1f88A ( 1 ) mnGtegpnfyVPfsnktgvVrsPfea-pQyyLaepwqFsmlAayMfl-l 2rh1 ( 29 ) devwvvgmgivmsl-i 4djhA ( 55 ) spaipviitavysv-v 4ej4 ( 41 ) rsasslalaiaitalYsa-v aaaaaaaaaaaa a 60 70 80 90 100 4iaq ( 60 ) tlaTtlsNafViatVyrt-rkLhtpanyLiasLAvTDllVSilVMpi--- 4lb4A ( 65 ) iipTigGNtlVilAVsle-kkLqyatnyFlmsLAvADllVGlfVMpi--- 4jkvA ( 238 ) GavTglcTlfTlaTFvadwrnsnrypaVILfyVNaCffvgSiGWlaQfmd 3vw7 ( 113 ) fvvSlplNimaivvFilk-mkvkkPAVVyMlhLAtADvlFVsv-Lpf--- 1f88A ( 48 ) imlGfpiNflTlyVTvqH-kkLrtpLNyILlnLAvADlfMVfgGFtT--- 2rh1 ( 44 ) vlaIvfgNvlVitAIakf-erLqtvtnyFItsLAcADlvMGlaVVpf--- 4djhA ( 70 ) fvvGlvgNslVmfVIiry-tkmktaTniYIfNLAlADalVTtT-Mpf--- 4ej4 ( 60 ) cavGllgNvlvmfgIvry-tkLktATniYIfNLAlADalATst-Lpf--- aaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaa aaa 110 120 130 140 150 4iaq ( 106 ) ----------Stmytv-tg-rWtlgqvvÇdfWlssDItCCTASIwHLCvi 4lb4A ( 111 ) ----------aLltim-feamWplplvlÇpawLflDVlfSTASIwHLCaI 4jkvA ( 288 ) garreIVçRadgTMRl-gE-pTsnetlsÇviiFviVYyAlMAGvvWFvvL 3vw7 ( 158 ) ----------kisYyfsgS-dWqfgselÇrfVtAaFYcnMYASIlLMtvI 1f88A ( 94 ) ----------TlyTSl-hG-yFvfgptGÇnlEGffATLGGEIaLwSLvvL 2rh1 ( 90 ) ----------gaahil-mk-mWtfgnfwçefWTSiDVlCVTASIeTLcvI 4djhA ( 115 ) ----------qstvyl-mn-sWpfgdvlÇkiVlsiDyyNMfTSIfTLtmM 4ej4 ( 105 ) ----------qsakyl-me-tWpfgellÇkaVlSidYyNMFTSIfTLtmM aaaaaa aaaaaaaaaaaaaaaaaaaaaaaaa 160 170 180 190 200 4iaq ( 144 ) AldrywaitdaveysakrtpkraavmialvwvfSisISl-pPf-fw-r-- 4lb4A ( 150 ) svdryiaIkkpiqanqynsratAfikitvVwliSigiAi-pVpikg-i-- 4jkvA ( 336 ) TyAWHTsFkalgttyqpgk-t--syfhllTwslPfvlTv-aIlavaqVDG 3vw7 ( 197 ) SiDrflAVvypm-----rtlgrAsftClaiwalAiagVv-pLllke-Qti 1f88A ( 132 ) aieRyvvvckpmsn-frfgenhAimgvafTwvmAlaCAa-pPlvgwSr-- 2rh1 ( 128 ) AvdryfAItspfkyqSlltknkArviilmvwivSgltSflpIqmhwyr-a 4djhA ( 153 ) SvdRyiaVchpvkaldfrtplkAkiinicIwllSssvGi-sAivlG-Gtk 4ej4 ( 143 ) SvDRyiavchpvkaldfrtpakAklinicIwvlAsgvGv-pimvmA-vtq aaaaaaaaa aaaaaaaaaaaaaaaaaaa aaa 210 220 230 240 250 4iaq ( 189 ) ------qa------s-eÇvv---n--------tdhilytvySTvgAFyfP 4lb4A ( 196 ) ------et-np-nni-tÇvL---t-------kerFgdfMlfgSlaAFftP 4jkvA ( 384 ) -DsV---------SG-IÇF-----------VGYknyryRagfVlapIglV 3vw7 ( 245 ) qvpglg-------it-Tçhdvlset----LlegyyayyfsafSavfFfvp 1f88A ( 178 ) ------YI-PE-GMQCSÇGI---DY-YTpheetnNesFViyMfvvHfiiP 2rh1 ( 177 ) -thqe-AinÇyaeet-çÇdf---f---------TnqayaiasSivSFyvp 4djhA ( 201 ) vredv-------dvi-eÇsl---qFpd-ddyswwdlfmkicVfifAfviP 4ej4 ( 191 ) prdg---------av-vÇml---qf-p-spswywdtvtkicvflfAfvvP aaaaaaaaaa aaa 260 270 280 290 300 4iaq ( 221 ) tllLialygrIyvears--r--------------ilma----arerkaTk 4lb4A ( 230 ) laiMivtyfltihALqkk---a---------------q--tisneqrask 4jkvA ( 412 ) livGgyfLirGvmtlfsIksn----hpglLsekaa---skinetMlrLgi 3vw7 ( 283 ) liiStvCyvsIirclss--s-a------------------anrskksrAl 1f88A ( 216 ) livIffcygqLvftvkea---AaS-------------a-ttqkaekevTr 2rh1 ( 212 ) lviMvfvYsrVfqeakr--q--------------l--k--fclkeHkaLk 4djhA ( 239 ) vliIivcytlMilrlksv---r-lls--------g---rekdrnlrritr 4ej4 ( 226 ) iliitvcyglMllrlrsv---r-----------------ekdrslrriTr aaaaaaaaaaaaaa aaaaaaa 310 320 330 340 350 4iaq ( 315 ) tLgiIlgaF-ivCWlpFFiiSlvmpi------------------------ 4lb4A ( 325 ) vlgivFflF-llmWcpFFitNitLvl-çd--sç---------------nq 4jkvA ( 455 ) fGflAfgfv-liTfscHfyDffnQae-We--rSFrdyVlçqançeiknr- 3vw7 ( 313 ) fLSaaVfcIFiiCFgpTNvlLiaHYsfl-sht-------------st--t 1f88A ( 253 ) MViiMviaF-liCWlpYAgvAfyIft-hq--gs---------------d- 2rh1 ( 274 ) tlgiIMgtF-tlcWlpFFiVNivhvi-qd---n---------------l- 4djhA ( 275 ) LVlvVVavF-vvcWtpIHifilveal-gs--------------------- 4ej4 ( 262 ) MVlvVvgaF-vvCWapIHifVivwtl-vd--in-----------rrd-p- aaaaaaaaa aaaaaaaaaaaaaaaa 360 370 380 390 400 4iaq ( 347 ) --hlaifdffTwlGYlNSliNPiiYtmsnedFkqafhkli-rfk 4lb4A ( 356 ) ttlqmlLeifvWiGYvSSGvNPlvyTlfnktFrdAfgrYi-tcnyr 4jkvA ( 513 ) -PsllvEkiNLfAmFgtGiaMStwvwtkatlliwrr-------twc 3vw7 ( 347 ) eaAYfaYLlcvCvSSiSCciDplIyyyAssec 1f88A ( 283 ) -fgPifMtipAFfAKtSAvyNPviYimmnkqFrnCmvttl-ccgknpstt 2rh1 ( 303 ) -irkevyillNwiGYvNSgfNpliYc-rspdfriAfqell-c-------- 4djhA ( 307 ) -aalssyyfcIalGytNSslNPilYafldenFkrcfrdfcf--p 4ej4 ( 295 ) -lvvaalhlcialGYaNSslNpvlYaflDenfkrc aaaaaaaaaaaaaaaaaaaaaaa aaaaaaa 410 4iaq 4lb4A 4jkvA 3vw7 1f88A ( 337 ) vsktetsqvapa 2rh1 ( 342 ) ------l 4djhA 4ej4
(1) Chong Wang et al., Science 3 May 2013: 340 (6132), 610-614
(2) Chong Wang et al., Nature 16 May 2013: 497, 338–343
(3) Kenji Mizuguch et al., Protein Science Nov 1998: 7 (11), 2469-2471
Updated: Somehow the HTML didn't render properly. -
Kinase Inhibitor Success in the Clinic - A snapshot Q2 2013
There is a lot of action in the approval of kinase inhibitors at the moment, and it is interesting to look at the attrition/survival of these through clinical trials, in the view above this is plotted as the number approved vs the number in the pipeline (the table takes care of mergers, compound acquisitions and so forth). The pale blue dotted line is the trend-line through the data, do not draw too much into this though...
It's interesting to see that Pfizer and GSK are doing relatively well, and Lilly and Roche (inc. Genentech) are doing relatively badly - across kinase inhibitors. But it doesn't make many approvals to make a difference to this!
Thanks to Krister Winnerberg for some cleanup of the kinase inhibitor dataset.
For clarification:
- this includes the indirect kinase inhibitors of the -rolimus class (7 approved, 1 of these Japan only).
- the total number of kinase inhibitors in the clinic in the dataset is 392, with 29 approved
- the Japan only inhibitor Fasudil is included in the set of approved small molecule inhibitors
-
New Drug Approvals 2013 - Pt. X - Trametinib (Mekinist®)
ATC code:L01XE15
Wikipedia:TrametinibChEMBL2103875
Trametinib is the first approved targeted MEK inhibitor. It inhibits the kinase catalytic activity of its targets, mitogen-activated extracellular signal regulated kinase 1 and 2 ( MAP2K1 AKA MEK1, Uniprot:Q02750) and MAP2K2 AKA MEK2, Uniprot:P36507).
The sequences of the targets are here:
>sp|Q02750|MP2K1_HUMAN Dual specificity mitogen-activated protein kinase kinase 1 OS=Homo sapiens GN=MAP2K1 PE=1 SV=2 MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEELELDEQQRKRLEAFLTQKQKV GELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHE CNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGRIPEQILGKVSIAVIKGLTYL REKHKIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLQGTHY SVQSDIWSMGLSLVEMAVGRYPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSY GMDSRPPMAIFELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV >sp|P36507|MP2K2_HUMAN Dual specificity mitogen-activated protein kinase kinase 2 OS=Homo sapiens GN=MAP2K2 PE=1 SV=1 MLARRKPVLPALTINPTIAEGPSPTSEGASEANLVDLQKKLEELELDEQQKKRLEAFLTQ KAKVGELKDDDFERISELGAGNGGVVTKVQHRPSGLIMARKLIHLEIKPAIRNQIIRELQ VLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKEAKRIPEEILGKVSIAVLRG LAYLREKHQIMHRDVKPSNILVNSRGEIKLCDFGVSGQLIDSMANSFVGTRSYMAPERLQ GTHYSVQSDIWSMGLSLVELAVGRYPIPPPDAKELEAIFGRPVVDGEEGEPHSISPRPRP PGRPVSGHGMDSRPAMAIFELLDYIVNEPPPKLPNGVFTPDFQEFVNKCLIKNPAERADL KMLTNHTFIKRSEVEEVDFAGWLCKTLRLNQPGTPTRTAV
Trametinib is administered as tablets containing trametinib dimethyl sulfoxide, the molecular formula C26H23FIN5O4 . C2H6OS with a molecular mass of 693.53. The molecular weight of trametinib itself is 615.4 and its AlogP is 3.18. Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L. Tmax occurs 1.5 hours after dosing, and mean oral bioavailavility is 72%. Trametinib is primarily metabolised by deamidation and subsequent clearance with a half life of 3.9 to 4.8 days, clearance is 4.9 L/hr. Trametinib is not an inhibitor or substrate for CYP or PGP systems, but is an inducer of CYP3A4 activity.
Standard dose is 2mg once daily, with lower doses recommended if side effects are observed. Significant, use limiting side effects are seen in many patients.
Mekinist is produced by GSK
The Prescribing Information is here. -
Drug impurities and similar and different pharmacological actions
A little something for the weekend. I've just escaped a busy day of childcare, and clear-out of our medicine cupboard. I threw away quite a few things that were two or three years out of date - now I would have quite happily taken them, but the bin seemed a better place. It's not like that suddenly on the date on the box, the active ingredient expires and transforms to a highly toxic compound. Given that temperature has a big effect on chemical rates, and that storage temperature is probably quite variable, the dates will tend to be really really conservative. For the majority of cases though, once would expect that there is simply less of the desired 'active' ingredient, and the drug will be (slightly) less efficacious.
It got me thinking though, what sort of pharmacologically active things will be in old pills, and above is a nice example of the active ingredient, impurities and degradation products for atorvastatin (which the eagle-eyed amongst you will spot that atorvastatin itself is the top left molecule). Most impurities look like they stand a fair chance of being HMGCoA reductase inhibitors too, and some look quite radically different, in fact heaven knows what they might interact with - but it is an interesting question to ask.
Of course, these are present in small quantities in the finished product, but their fractional occurrence is like a watermark, that can detect variations in process, storage conditions and so forth - even counterfeit drugs.
If anyone is aware of cases where there is a marked and profound activity for a degradation product, please put it in the comment section. -
Paper: The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases
Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.
Data from studies involving the Malaria Box will be in ChEMBL and the ChEMBL Malaria portal.
%A T. Spangenberg %A J.N. Burrows %A P. Kowalczyk %A S. McDonald %A TNC Wells %D 2013 %T The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases %J PLoS ONE %V 8 %P e62906 %O doi:10.1371/journal.pone.0062906
-
Clustering of a few chemical databases
Above is a PCA plot of a number (17) of databases contained within UniChem (click image to make it bigger). The plot contains 30 odd % of the variance, so certainly not the complete picture, and pretty close to the dignity level of plotting in 2D! Check out https://www.ebi.ac.uk/unichem for more details on the databases and versions, the distance metric reflects the fraction of shared standard InChI keys.
Anyway, it's pretty interesting, there are arguably three arms to this...
- Top left - screening compound databases (zinc, euos and emolecules)
- Bottom centre - patent databases (patents, ibm and surechem)
- Centre right - drug databases (drugbank, et al)
In the middle is Chembl itself, which sort of makes sense, as there will be fractionally more overlap with patent db's, available compounds, and drugs. -
USAN Watch: June 2013
The USANs for June 2013 have recently been published.
USAN Research Code InChIKey (Parent) Drug Class Therapeutic class Target beraprost ML-1229CTPOHARTNNSRSR-OUKQBFOZSA-N therapeutic synthetic small molecule PGI2R esketamine hydrochloride YQEZLKZALYSWHR-ZDUSSCGKSA-N therapeutic synthetic small molecule NMDAR evolocumab AMG-145 n/a therapeutic monoclonal antibody PCSK9 idelalisib
GS-1101, CAL-101IFSDAJWBUCMOAH-HNNXBMFYSA-N therapeutic synthetic small molecule PI3K rivipansel, rivipansel hydrochloride GMI-1070, PF-06460031n/a therapeutic natural product-derived small molecule selectin -
New Drug Approvals 2013 - Pt. IX - Dabrafenib mesylate (Tafinlar®)
ATC code: L01XE15
Wikipedia: Dabrafenib
On May 29th 2013 the FDA approved dabrafenib mesylate (trade name: Tafinlar®, research codes GSK-2118436A and GSK-2118436B) for the treatment of patients with unresectable metastatic melanoma harbouring the BRAF V600E mutation. In clinical trials, dabrafenib showed improved progression-free survival (PFS) over the comparator dacarbazine (median PFS 5.1 months for dabrafenib compared to 2.7 months for dacarbazine). Moreover, in a multicentre open-label Phase II trial dabrafenib showed effectiveness on brain metastases of melanoma regardless of whether the patients had been previously treated.
As with the previously approved BRAF inhibitor, vemurafenib, the major side effect of dabrafenib is the emergence of malignant cutaneous squamous cell carcinomas and keratoacanthomas.
The main molecular target for dabrafenib is the human mutant serine/threonine kinase, BRAF (Uniprot for wild type protein: P15056). Dabrafenib potently inhibits multiple mutant BRAF species including V600E at 0.65 nM, V600K at 0.5 nM and V600D at 1.84 nM. It also inhibits wild type BRAF at 3.2 nM and wild type CRAF at 5 nM.
Dabrafenib is administered orally as capsules containing the dabrafenib mesylate salt. Dabrafenib freebase (ChEMBL:CHEMBL2028663) has a molecular weight of 519.6 and AlogP of 5.38. The molecular formula of dabrafenib is C23H20F3N5O2S2. After oral administration, the median time to reach peak plasma concentration (Tmax) is 2 hours; the mean absolute bioavailability is 95% and the mean terminal half-life is 8 hours after oral administration.
Tafinlar® is produced by Glaxosmithkline
The full Prescribing Information is here
bissan
