Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

Abstract

St r uct ur al si m i l ar i t i es bet w een som e com m on f l uor oph or es used i n bi ol ogy an d m ar k et ed dr u gs, en dogen ou s m et abol i t es, an d n at u r al pr odu ct s St ev e O'Hagan 1,2 , Dou gl as B. Kel l 1,2,3,4 * 1 School of Chem istr y, 2 M anchester Insti tute of Bi otechnology, The Uni ver si ty of M anchester , 131 Pr incess St, M anchester M1 7DN, UK 3 (and pr esent addr ess): Depar tm ent of Biochem istr y, Institute of Integr ative Biology, Biosciences Building, Univer sity of Liver pool, Cr ow n Str eet, Liver pool L69 7ZB, UK. 4 Novo Nor di sk Foundation Centr e for Biosustainability, Technical Univer sity of Denm ar k, Building 220, Kem itor vet, 2800 Kgs. Lyngby, Denm ar k * Cor r espondence: Douglas Kell, Em ai l: dbk@liv.ac.uk; ABSTRACTBackgr ound: It is kn ow n th a t a t lea st som e flu or op h or es ca n a ct a s 'su r r oga te' su b str a tes for solu te ca r r ier s (SLCs) in volved in p h a r m a ceu tica l d r u g u p ta ke, a n d th is p r om iscu ity is ta ken to r eflect a t lea st a cer ta in str u ctu r a l sim ila r ity. As p a r t of a com p r eh en sive stu d y seekin g th e 'n a tu r a l' su b str a tes of 'or p h a n ' tr a n sp or ter s th a t a lso ser ve to ta ke u p p h a r m a ceu tica l d r u gs in to cells, w e h a ve n oted th a t m a n y d r u gs b ea r str u ctu r a l sim ilar ities to n a tu r al pr od u cts. A cu r sor y in sp ection of com m on flu or op h or es in d ica tes th a t th ey too a r e su r p r isin gly 'd r u g-like', a n d th ey a lso en ter a t lea st som e cells. Som e a r e a lso kn ow n to b e su b str a tes of efflu x tr a n sp or ter s. Con seq u en tly, w e sou gh t to a ssess th e str u ctu r a l sim ila r ity of com m on flu or op h or es to m a r keted d r u gs, en d ogen ou s m a m m a lia n m eta b olites, a n d n a tu r a l p r od u cts. We u sed a set of som e 150 flu or op h or es. Results: Th e gr ea t m a jor ity of flu or op h or es tested exh ib ited sign ifica n t sim ila r ity (Ta n im oto sim ila r ity > 0.75) to a t lea st on e d r u g a s ju d ged via descr ip tor p r op er ties (esp ecia lly th eir a r om a ticity, for id en tifia b le r ea son s th a t w e exp la in ), b y m olecu la r fin ger p r in ts, b y visu a l in sp ection , a n d via th e "q u a n tita tive estim a te of d r u g liken ess" tech n iq u e. It is con clu d ed th a t th is set of flu or op h or es d oes over la p a sign ifica n t p a r t of b oth d r u g sp a ce a n d n a tu r a l p r od u cts sp a ce. Con seq u en tly, flu or op h or es d o in d eed offer a m u ch w id er op p or tu n ity th a n h a d p ossib ly b een r ea lised to b e u sed a s su r r oga te u p ta ke m olecu les in th e com p etitive or tr a n s-stim u la tion a ssa y of m em br a n e tr a n sp or ter a ctivities.KEYW ORDS: d r u gs -n atu r a l p r od u cts -flu or op h or es -sim ila r ity -ch em in for m a tics -Ta n im oto d ista n ce ABBREVI ATI ONS PCA, Pr in cip a l Com p on en ts An a lysis; QED, Qu a n tita tive Estim a te of Dr u g-liken ess; QSAR, Qu a n ...

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