Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs

Shultz, Michael D.

doi:10.1021/acs.jmedchem.8b00686

Cited by 349 publications

(338 citation statements)

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“…Ap ossible explanation would be the dominating lipophilic contribution by the 4-biphenyl substituent together with conformationalr estraintsd ue to the b-annelation. Furthermore,n oneo fthed escribed DHPs violates the extended 'rule-of-five' principles ( Table 2), [17] justifying more extended biological profiling and in vivo experimental pharmacology.…”

Section: Lipophilicity and Solubilitymentioning

confidence: 98%

Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1,4‐Dihydropyridine‐Class TGFβ Inhibitors

et al. 2019

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Innovative therapeutic modalities for pharmacological intervention of transforming growth factor β (TGFβ)‐dependent diseases are of great value. b‐Annelated 1,4‐dihydropyridines (DHPs) might be such a class, as they induce TGFβ receptor type II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study. It was possible to install polar functionalities and bioisosteric moieties at distinct sites of the molecules while maintaining TGFβ‐inhibitory activities. The introduction of a 2‐amino group or 7‐N‐alkyl modification proved to be successful strategies. Aqueous solubility was improved by up to seven‐fold at pH 7.4 and 200‐fold at pH 3 relative to the parent ethyl 4‐(biphenyl‐4‐yl)‐2,7,7‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate. The therapeutic potential of the presented DHPs was further underscored in view of a potential dual mode of action: The differentiation of committed human iPSC‐derived cardiac progenitor cells (CPCs) was potently stimulated, and the rescue of cardiac fibrosis phenotypes was observed in engineered heart tissue (EHT) constructs.

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Section: Lipophilicity and Solubilitymentioning

confidence: 98%

Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1,4‐Dihydropyridine‐Class TGFβ Inhibitors

et al. 2019

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“…optimal for a small molecule with good pharmacokinetic properties [34,35]. Contrary to the classical perspective, it is noteworthy that a G4 ligand that lacks traditional 'drug-like' properties has shown significant accumulation and efficacy in tumour xenografts of human cancers [29].…”

Section: Glossarymentioning

confidence: 99%

The Structure and Function of DNA G-Quadruplexes

Spiegel

Adhikari

Balasubramanian

2020

Trends in Chemistry

639

568

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Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery. Beyond the DNA Double HelixA chemist's perspective on the function of a molecule, or a system of molecules, is typically led by a consideration of how molecular structure dictates function. The most widely recognised DNA structure is that of the classical DNA double helix [1], which defines a structural basis for the genetic code via defined base-pairing. Yet, it is evident that DNA is structurally dynamic and capable of adopting alternative secondary structures. One such class of DNA secondary structure is the four-stranded Gquadruplex (G4). Herein, we discuss some of the key scientific history that has shaped our understanding of this structural motif, its probable functions in biology, and major unanswered questions that remain to be solved.

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“…Bicker ton a n d collea gu es [74] in tr od u ced th e con cep t of th e q u a n tita tive estim a te of d r u g-liken ess (QED) (b u t see [75]), a n d it is of in ter est to see h ow 'd r u g-like' ou r fou r cla sses of m olecu le a r e b y th eir cr iter ia . Fig 5A sh ow s th e d istr ib u tion of QED d r u g-liken esses for m a r keted d r u gs, for Recon 2 m eta b olites, for ou r selected flu or op h or es, a n d for a sa m p le of 2000 m olecu les fr om UNPD.…”

Section: Resultsmentioning

confidence: 99%

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

O’Hagan

Kell

2019

Preprint

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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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Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs

Cited by 349 publications

References 72 publications

Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1,4‐Dihydropyridine‐Class TGFβ Inhibitors

Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1,4‐Dihydropyridine‐Class TGFβ Inhibitors

The Structure and Function of DNA G-Quadruplexes

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

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