Abaphandi bakhe ithala leencwadi elikhulu leedokhi elinokuthi lincede ekufumaneni ngokukhawuleza amayeza amatsha kunye nonyango
Ukuphuhlisa amachiza amatsha kunye namayeza ezigulo, indlela enokubakho 'kukucoca' inani elikhulu leemolekyuli zonyango kunye nokuvelisa 'iinkokeli'. Ukufunyanwa kweziyobisi yinkqubo ende kwaye icela umngeni. Ukukhawulezisa inkqubo yokufumanisa ichiza elitsha, iinkampani zamachiza zisebenzisa iziseko ezingundoqo (ezibizwa ngokuba zii-scaffolds) zeemolekyuli esele zaziwa njengechiza ukusukela oko ukuhlola imolekyuli entsha kunzima kwaye kuyabiza.
Indlela yokufumanisa iziyobisi esekwe kulwakhiwo
Imodeli yokubala elandelwa ngu enembonakalo yenyani okanye ngaphakathi silico ukufakwa kweekhompawundi zemichiza kwiprotheyini ekujoliswe kuyo yindlela ethembisayo yokukhawulezisa ichiza Ukufumanisa kunye nokunciphisa iindleko zaselabhoratri. I-molecular docking ngoku iyinxalenye ebalulekileyo ye-computer-aid-structure-based uyilo lweziyobisi. Iinkqubo ezininzi zesoftware ezifana ne-AutoDock kunye ne-DOCK ziyafumaneka ezinokuthi zizenzele ngokuzimeleyo kwiinkqubo zekhompyuter yoqwalaselo oluphezulu. Ulwakhiwo lwe-3-D macromolecular ye-receptor ekujoliswe kuyo ithathwa kwindlela yovavanyo efana ne-X-ray crystallography okanye nge-in. silico imodeli yehomology. I-ZINC ngumthombo ovulekileyo wesiseko sedatha ye-230 yezigidi zeekhompawundi ezifumanekayo ngokurhweba kwifomathi ye-3D ekhutshelwayo enokuthi isetyenziswe kwi-docking ye-molecular kunye ne-virtual screening Post docking, iimolekyuli zinokuthi zihlalutywe ngokubonakalayo malunga nendlela eziphatha ngayo kwiprotheni ye-receptor. Olu hlalutyo lubandakanya amandla abo okubopha ababalwayo kunye nokuhambelana kwabo kwe-3D. Ukusebenzisana phakathi kweprotheyini edibeneyo kunye nejoliswe kuyo kunokubonelela ngolwazi malunga neempawu ze-pharmacological zaloo molekyuli. Imodeli yokubala kunye ne-docking inika ithuba lokuhlola inani elikhulu leemolekyuli ngaphambi kokuba uqhubele phambili kwilabhoratri emanzi, ukucutha izixhobo njengoko kufuneka kusekwe isiseko sexesha elinye kuphela.
Ukwakha kunye nokusetyenziswa kwethala leencwadi elikhulu kwi-silico docking
Kwisifundo esitsha esishicilelwe kwi Nature abaphandi bahlalutya i-docking esekelwe kwisakhiwo esekwe kwithala leencwadi elinomlinganiselo omangalisayo we-170 yezigidi zeemolekyuli. Eli thala leencwadi lisekelwe kuphononongo lwangaphambili olusebenzise indlela yokudotshwa esekwe kulwakhiwo ukuze kuqondwe iziphumo zechiza le-antipsychotic kunye ne-LSD docking kwii-receptors zabo. Olu phononongo luncede ukuyila ngempumelelo isibulali-ntlungu esinokuthi sibophe ngokukhetha i-analgesic thabatha iziphumo ebezingalindelekanga ze-morphine.
Izigidi zeemolekyuli ezahlukeneyo ezifana neziyobisi ziyaziwa ukuba zikhona kodwa azifikeleleki ngenxa yothintelo olujongene nolwakhiwo lwamathala eencwadi eemolekyuli. Ubuchule bokudotshwa obubonakalayo bunokubonisa izinto ezingeyonyani ezibizwa ngokuba 'yi-decoys' enokuthi ifakwe kakuhle kuyo silico kodwa abanakukwazi ukufikelela kwisiphumo esifanayo kuvavanyo lwaselabhoratri kwaye banokungasebenzi ngokwebhayoloji. Ukoyisa le meko, abaphandi bagxile kwiimolekyuli ezazivela kwindawo efanelekileyo kwaye baqonda ukusabela kweekhemikhali ezili-130 ngokusebenzisa iibhloko zokwakha zekhemikhali ezahlukeneyo ezingama-70,000. Ithala leencwadi lahluke kakhulu njengoko limele i-10.7 yezigidi zeescaffolds ebezingeyonxalenye yalo naliphi na elinye ithala leencwadi. Ezi khompawundi ziye zafaniswa kwikhompyuter kwaye oku kube negalelo ekukhuleni kwethala leencwadi kwaye kwanciphisa ubukho bezinto ezikhohlisayo.
Abaphandi baye benza iimvavanyo ze-docking besebenzisa i-X-ray crystal structures ye-receptors ezimbini, okokuqala i-D4 dopamine receptor-iprotheyini ebalulekileyo yosapho lwe-G protein-coupled receptors eyenza izenzo ze-dopamine - i-brain chemical messenger. I-D4 receptor kucingelwa ukuba idlala indima ephambili kulwazi kunye neminye imisebenzi yengqondo echaphazeleka ngexesha lokugula ngengqondo. Okwesibini, baye benza idocking kwi-enzayimu i-AmpC engunobangela ophambili wokuxhathisa amayeza athile okubulala iintsholongwane kwaye kunzima ukuyivala. Iimolekyuli eziphezulu ezingama-549 ukusuka kwi-docking ye-D4 receptor kunye ne-44 ephezulu evela kwi-enzyme i-AmpC yadweliswa, yaxutywa kwaye yavavanywa kwilebhu. Iziphumo zibonise ukuba iimolekyuli ezininzi zibopha ngamandla kwaye ngokuthe ngqo kwi-D4 receptor (ngelixa ingekho kwi-D2 kunye ne-D3 i-receptors ehambelana ngokusondeleyo ne-D4). Imolekyuli enye, isibophelelo esomeleleyo se-AmpC enzyme, ibingaziwa ukuza kuthi ga ngoku. Iziphumo zedocking zazibonisa iziphumo zovavanyo kwi-bioassay.
Ithala leencwadi elisetyenzisiweyo kuphononongo lwangoku likhulu kwaye lahlukene kwaye ke iziphumo bezinamandla kwaye zicace gca ziqinisekisa ukuba i-docking ebonakalayo kunye namathala eencwadi amakhulu inokuqikelela ngcono kwaye ngaloo ndlela iphumelele izifundo ezininzi usebenzisa amathala eencwadi amancinci. Iikhompawundi ezisetyenzisiweyo kolu phando zifumaneka ngokukhululekileyo kwithala leencwadi leZINC elandiswayo kwaye kulindeleke ukuba likhule liye kumanqaku ebhiliyoni e-1 ngo-2020. Inkqubo yokuqala ukufumanisa isikhokelo kwaye ukuyila ibe sisiyobisi ihlala ingumngeni, kodwa ithala leencwadi elikhulu. iyakubonelela ngofikelelo kwiikhompawundi zemichiza emitsha ezinokukhokelela kwiziphumo ezimangalisayo. Olu phononongo lubonisa kwi-silico ukwenza imodeli yekhompyutha kunye nokudokwa kusetyenziswa amathala eencwadi anamandla njengendlela ethembisayo yokufumanisa iikhompawundi ezintsha ezinokubakho zonyango kwizigulo ezahlukeneyo.
***
{Unokufunda iphepha lokuqala lophando ngokunqakraza ikhonkco le-DOI elinikwe ngezantsi kuluhlu lwemithombo ecatshulweyo (s)}
Umthombo (s)
1. ULyu J et al. 2019. Ithala leencwadi elikhulu kakhulu lokufumana iikhemotypes ezintsha. indalo.
https://doi.org/10.1038/s41586-019-0917-9
2. Sterling T kunye no-Irwin JJ 2015. ZINC 15 - Ligand kweFidi kuye wonke umntu. J. Chem. Inf. Umzekelo.. 55. https://doi.org/10.1021/acs.jcim.5b00559
3. http://zinc15.docking.org/
