Medicinal chemistry of target family-directed masterkeys

Müller, Gerhard

doi:10.1016/s1359-6446(03)02781-8

Cited by 211 publications

(118 citation statements)

References 39 publications

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“…This observation also suggests that chemotypes are frequently utilized in medicinal chemistry having a high probability of activity against different targets. Preferred chemotypes have often been considered as target class-or family-directed (privileged) structural motifs (15,16). However, scaffolds have also been identified that display a strong tendency to be active across different families (17).…”

Section: Discussionmentioning

confidence: 99%

Rationalizing Structure and Target Relationships between Current Drugs

Bajorath

2012

AAPS J

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Abstract. A recent analysis of structure and target relationships between current drugs and bioactive compounds has revealed that only a small fraction of drugs that are active against the same or overlapping targets are involved in substructure relationships and/or share the same topology. By contrast, structurally related drugs displayed a tendency to preferentially act against different targets. For bioactive compounds, opposite trends were observed. These surprising findings arising from the global analysis have now been examined in detail by analyzing structure and target relationships between drugs at the level of individual targets and individual drugs and by comparing the results of local (target-or drug-based) and global relationship analysis. On the basis of target-based analysis, on average, only 14% of drugs active against a given target form well-defined structural relationships. In addition, drug-based analysis revealed that on average 72% of all structurally related drugs have no or at most 20% target overlap. Taken together, the results of our current analysis at the level of single targets and drugs rationalize their unexpected structure and target relationships in a consistent manner. These findings also have implications for ligand binding characteristics of popular drug targets and for frequently observed polypharmacological drug behavior.

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Section: Discussionmentioning

confidence: 99%

Rationalizing Structure and Target Relationships between Current Drugs

Bajorath

2012

AAPS J

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“…With the help of the master key concept, which uses privileged structures like quinazolines for drug development, it may be possible to develop pUL97-specific kinase inhibitors (22). On the other hand, it might be rather beneficial, with respect to efficacy and resistance formation, for an anti-HCMV drug to block both pUL97 and EGFR, since EGFR represents an HCMV binding and signaling receptor (28).…”

Section: Discussionmentioning

confidence: 99%

Novel Chemical Class of pUL97 Protein Kinase-Specific Inhibitors with Strong Anticytomegaloviral Activity

Herget

Freitag

Morbitzer

et al. 2004

Antimicrob Agents Chemother

142

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Human cytomegalovirus (HCMV) is a major human pathogen frequently associated with life-threatening disease in immunosuppressed patients and newborns. The HCMV UL97-encoded protein kinase (pUL97) represents an important determinant of viral replication. Recent studies demonstrated that pUL97-specific kinase inhibitors are powerful tools for the control of HCMV replication. We present evidence that three related quinazoline compounds are potent inhibitors of the pUL97 kinase activity and block in vitro substrate phosphorylation, with 50% inhibitory concentrations (IC 50 s) between 30 and 170 nM. Replication of HCMV in primary human fibroblasts was suppressed with a high efficiency. The IC 50 s of these three quinazoline compounds (2.4 ؎ 0.4, 3.4 ؎ 0.6, and 3.9 ؎ 1.1 M, respectively) were in the range of the IC 50 of ganciclovir (1.2 ؎ 0.2 M), as determined by the HCMV green fluorescent protein-based antiviral assay. Importantly, the quinazolines were demonstrated to have strong inhibitory effects against clinical HCMV isolates, including ganciclovir-and cidofovir-resistant virus variants. Moreover, in contrast to ganciclovir, the formation of resistance to the quinazolines was not observed. The mechanisms of action of these compounds were confirmed by kinetic analyses with infected cells. Quinazolines specifically inhibited viral early-late protein synthesis but had no effects at other stages of the replication cycle, such as viral entry, consistent with a blockage of the pUL97 function. In contrast to epithelial growth factor receptor inhibitors, quinazolines affected HCMV replication even when they were added hours after virus adsorption. Thus, our findings indicate that quinazolines are highly efficient inhibitors of HCMV replication in vitro by targeting pUL97 protein kinase activity.

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“…According to the definition that is most widely applied in medicinal chemistry, originally introduced by Bemis and Murcko (3), scaffolds are extracted from compounds by removing all substituents (R-groups), while retaining aliphatic linkers between ring systems (3). One of the primary goals of scaffold analysis is the association of molecular building blocks or core structures with specific biological activities (4)(5)(6)(7). Knowledge of such preferred core structures is thought to be of high relevance for target-or target family-directed compound design (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

“…One of the primary goals of scaffold analysis is the association of molecular building blocks or core structures with specific biological activities (4)(5)(6)(7). Knowledge of such preferred core structures is thought to be of high relevance for target-or target family-directed compound design (2)(3)(4). Scaffolds have also been monitored in compounds at different pharmaceutical development stages including leads, clinical trials compounds, experimental drugs, and marketed drugs (8).…”

Section: Introductionmentioning

confidence: 99%

Structural and Activity Profile Relationships Between Drug Scaffolds

Bajorath

2015

AAPS J

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Abstract. Core structures of current drugs have been assembled and their structural relationships and activity profiles have been explored. Drug scaffolds were frequently involved in different types of structural relationships. In addition, a variety of activity profile relationships between structurally related drug scaffolds were detected, ranging from closely overlapping to distinct profiles. Furthermore, when structural and activity profile relationships of scaffolds from drugs and bioactive compounds were compared, systematic differences were detected. Consensus activity profiles were introduced as a new approach for the qualitative and quantitative assessment of activity similarity of structurally related drugs represented by the same scaffold. On the basis of consensus activity profiles, scaffolds representing drugs active against distinct targets can be distinguished from drugs having similar target profiles and target hypotheses can be derived for individual drugs. Given the results of our analysis, drug scaffolds have been systematically organized according to structural and activity profile criteria. Our scaffold sets and the associated information are made freely available.

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Medicinal chemistry of target family-directed masterkeys

Cited by 211 publications

References 39 publications

Rationalizing Structure and Target Relationships between Current Drugs

Rationalizing Structure and Target Relationships between Current Drugs

Novel Chemical Class of pUL97 Protein Kinase-Specific Inhibitors with Strong Anticytomegaloviral Activity

Structural and Activity Profile Relationships Between Drug Scaffolds

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