In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline--and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.
S tsel'iu poiska novykh ingibitorov kliuchevogo fermenta biosinteza androgenov – 17a-gidroksilazy-17,20-liazy (tsitokhroma R450 17A1, CYP17A1) – proveden molekuliarnyĭ doking shesti novykh proizvodnykh oksazolin- soderzhashchikh proizvodnykh 17(20)E-pregna-5,17(20)-diena v aktivnyĭ tsentr kristallicheskoĭ struktury CYP17A1 (pdb 3ruk). Rezul'taty svidetel'stvuiut, chto: 1) obrazovanie kompleksa s CYP17A1 vyzyvaet izomerizatsiiu vsekh soedineniĭ v énergeticheski menee vygodnyĭ 17(20)Z-izomer; 2) steroidnyĭ fragment vsekh soedineniĭ lokalizuetsia prakticheski odinakovo; 3) struktura oksazolinovogo fragmenta znachitel'no vliiaet na ego polozhenie otnositel'no gema i énergiiu obrazovaniia kompleksa; 4) koordinatsiia atoma azota oksazolinovogo tsikla i atoma zheleza gema vozmozhna tol'ko pri realizatsii 17(20)Z-konformatsii ligada s anti-orientatsieĭ dvoĭnykh sviazeĭ 17(20) i C=N; 5) nalichie dvukh zamestiteleĭ pri S4’ oksazolinovogo tsikla znachitel'no ukhudshaiut sviazyvanie liganda; 6) oksazolin- i benzoksazol-soderzhashchie proizvodnye 17(20)E-pregna-5,17(20)-diena sposobny éffektivno podavliat' kataliticheskuiu aktivnost' SYP17A1 i mogut predstavliat' interes v kachestve osnovy dlia razrabotki novykh preparatov dlia lecheniia androgen-zavisimykh onkologicheskikh zabolevaniĭ.
Keywords: cytochrome P450 17A1; electrochemistry; inhibitors; molecular modeling; nitrogen-containing derivatives of 17(20)E-pregna-5,17(20)-diene; structure-activity relationships.