Pharmacophore modeling and parallel screening for PPAR ligands

Markt, Patrick; Schuster, Daniela; Kirchmair, Johannes; Laggner, Christian; Langer, Thierry

doi:10.1007/s10822-007-9140-0

Cited by 65 publications

(72 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings open a new avenue for the study of PD-1-mediated T-cell regulation as well as a combinatorial treatment strategy for patients with cancers and possibly infectious diseases who are less sensitive to PD-1 blockade therapy alone. Notably, oltipraz and bezafibrate have already been used as clinical medicines, being applicable to clinical studies of combination therapy with PD-1 mAb (60,61). The current study also suggests that mitochondrial activation parameters could be clinical biomarker candidates for distinction between responders and nonresponders to PD-1 blockade therapy.…”

Section: Discussionmentioning

confidence: 63%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

View full text Add to dashboard Cite

Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

show abstract

Section: Discussionmentioning

confidence: 63%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

340

287

View full text Add to dashboard Cite

show abstract

“…[63] Increasing the target space did not decrease the performance of the profiling method since the right target was ranked among the top 5 scorers for 71 % of true actives. [63] …”

Section: Proof Of Conceptmentioning

confidence: 99%

Structure‐Based Approaches to Target Fishing and Ligand Profiling

Rognan¹

2010

Molecular Informatics

142

111

View full text Add to dashboard Cite

Chemogenomics is an emerging interdisciplinary field aiming at identifying all possible ligands of all possible targets. If one groups targets in columns and ligands in rows, chemogenomic approaches to drug discovery just fill the interaction matrix. Since experimental data do not suffice, several computational methods are currently actively developed to supplement time-consuming and costly experiments. They are either designed to fill rows and thus profile a ligand towards a heterogeneous set of targets (target profiling) or to fill columns and thus identify novel ligands for an existing target (standard virtual screening). At the interface of both strategies are now true chemogenomic computational methods filling well defined areas in the matrix. The present review will focus on (protein) structure-based approaches and illustrates major advances in this novel exciting field which is supposed to massively impact rational drug design in the next decade.

show abstract

“…31 Branch I, surrounded by H3, H5, H11 and H12, shows mainly hydrophilic character and provides an activation function-2 surface. The hydrophilic head group of rosiglitazone occupies this branch and forms a hydrogen-bonding network with key residues Ser289, His323, Tyr327, His449 and Tyr473.…”

Section: Binding Mode Of Telmisartan In the Pparcmentioning

confidence: 99%

Structural basis for telmisartan-mediated partial activation of PPAR gamma

et al. 2012

View full text Add to dashboard Cite

Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARc). To understand how telmisartan partially activates PPARc, we determined the ternary complex structure of PPARc, telmisartan, and a coactivator peptide from steroid receptor coactivator-1 at a resolution of 2.18 Å . Crystallographic analysis revealed that telmisartan exhibits an unexpected binding mode in which the central benzimidazole ring is engaged in a non-canonical-and suboptimal-hydrogen-bonding network around helix 12 (H12). This network differs greatly from that observed when full-agonists bind with PPARc and prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding with telmisartan results in a less stable H12 that in turn leads to attenuated coactivator binding, thus explaining the mechanism of partial activation.

show abstract

Pharmacophore modeling and parallel screening for PPAR ligands

Cited by 65 publications

References 41 publications

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Structure‐Based Approaches to Target Fishing and Ligand Profiling

Structural basis for telmisartan-mediated partial activation of PPAR gamma

Contact Info

Product

Resources

About