The influence of drug-like concepts on decision-making in medicinal chemistry

Leeson, Paul D.; Springthorpe, Brian

doi:10.1038/nrd2445

Cited by 2,065 publications

(1,898 citation statements)

References 51 publications

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“…Efficiency metrics such as lipophilic ligand efficiency (LLE), 10 ligand efficiency (LE), 11 and group efficiency (GE) 12 were calculated and are summarized in Table 1.…”

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confidence: 99%

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Lanier

Pickens

Bigi

et al. 2017

ACS Med. Chem. Lett.

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Apoptosis signal-regulating kinase 1 (ASK1/ MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury. KEYWORDS:Apoptosis signal-regulating kinase 1 (ASK1), structure-based drug design (SBDD), cardiac injury A poptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) family member residing upstream of both Jun N-terminal kinase (JNK) and p38. ASK1 is capable of activating JNK and P38 via the phosphorylation of intermediate kinases. ASK1 plays a role in the mammalian cell stress response and the induction of apoptotic cell death. It also contributes to a range of systemic diseases including heart failure 1 and acute ischemia/reperfusion injury, by reducing structural and functional integrity of the mitochondria in cardiac cells. 2−4 ASK1-deficient mice display reduced levels of cardiomyocyte apoptosis, hypertrophy, and interstitial fibrosis. 5 Thus, selective inhibition of ASK1 represents an attractive strategy for slowing or potentially reversing harmful tissue changes associated with various forms of heart failure.Using ASK1 structural information and deconstruction of known ASK1 inhibitors such as 1 and 2 (Figure 1), our research team generated a novel, potent, and orally bioavailable ASK1 inhibitor with favorable physicochemical properties to help further elucidate the role of ASK1 in cardiac injury. Compound 1 was an early lead for Takeda's ASK1 inhibitor program. 6 Compound 2 (GS-4997, Gilead Sciences) is a clinical stage ASK1 inhibitor, which has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis. 7 Key structural features with respect to ligand interactions within the ATP binding site were identified using our internal database as well as public domain crystal structures of small molecules in ASK1 and published pharmacophore models. 8,9 Figure 1 illustrates the cocrystal structure of 1 in hASK1 (PDB: 3VW6) and highlights the key interactions between 1 and the ASK1 ATP binding pocket. Binding to the kinase hinge is characterized by a hydrogen bonding interaction with the

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“…Efficiency metrics such as lipophilic ligand efficiency (LLE), 10 ligand efficiency (LE), 11 and group efficiency (GE) 12 were calculated and are summarized in Table 1.…”

mentioning

confidence: 99%

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Lanier

Pickens

Bigi

et al. 2017

ACS Med. Chem. Lett.

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“…The ligand−lipophilicity efficiency (LLE) 22 evaluation of the benzamide series (Table 1, column 5) establishes the nido-7,8-carborane Cs·5 as a good lead candidate (LLE ≥ 5). Despite its equivalent in vitro and in vivo results, the higher lipophilicity of cubanyl 2 suggests it will be less bioavailable and may be more susceptible to metabolism.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

The First CNS-Active Carborane: A Novel P2X₇ Receptor Antagonist with Antidepressant Activity

Wilkinson¹,

Gunosewoyo²,

Barron³

et al. 2014

ACS Chem. Neurosci.

127

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“…The evaluation of further metrics, such as for example, estimated ligand‐lipophilicity efficiency,17 will help to decrease the number of proposed macrocycles to a number manageable for FEP+.…”

Section: Discussionmentioning

confidence: 99%

Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation

et al. 2017

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Macrocycles play an increasing role in drug discovery, but their synthesis is often demanding. Computational tools that suggest macrocyclization based on a known binding mode and that estimate the binding affinity of these macrocycles could have a substantial impact on the medicinal chemistry design process. For both tasks, we established a workflow with high practical value. For five diverse pharmaceutical targets we show that the effect of macrocyclization on binding can be calculated robustly and accurately. Applying this method to macrocycles designed by LigMac, a search tool for de novo macrocyclization, our results suggest that we have a robust protocol in hand to design macrocycles and prioritize them prior to synthesis.

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The influence of drug-like concepts on decision-making in medicinal chemistry

Cited by 2,065 publications

References 51 publications

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

The First CNS-Active Carborane: A Novel P2X₇ Receptor Antagonist with Antidepressant Activity

Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation

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The influence of drug-like concepts on decision-making in medicinal chemistry

Cited by 2,065 publications

References 51 publications

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

The First CNS-Active Carborane: A Novel P2X7 Receptor Antagonist with Antidepressant Activity

Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation

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The First CNS-Active Carborane: A Novel P2X₇ Receptor Antagonist with Antidepressant Activity