2013 Philip S. Portoghese Medicinal Chemistry Lectureship: Drug Discovery Targeting Allosteric Sites

Lindsley, Craig W.

doi:10.1021/jm5011786

Cited by 28 publications

(66 citation statements)

References 88 publications

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“…Allosteric ligands have been noted to be especially sensitive to even slight changes in structural features [29,30] and we have previously shown that the quaternary derivative of amiodarone (NEA; fig. 1 ) has very different properties from amiodarone (see below).…”

Section: Discussionmentioning

confidence: 99%

Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

et al. 2016

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We have previously reported that amiodarone interacts with a novel allosteric site on muscarinic receptors. Amiodarone's most striking effect is to enhance the maximal response elicited by muscarinic agonists at the M₁, M₃, and M₅ receptors. Furthermore, the quaternary analog N-ethylamiodarone (NEA) is inhibitory at these receptors and appears to compete with amiodarone at that allosteric site. In the present studies, we show that dronedarone also modulates Gq-mediated responses at M₁ and M₃, although in a more discriminating manner. For example, dronedarone markedly enhances pilocarpine-stimulated release of arachidonic acid from CHO cells, via the M₃ receptor subtype, but does not affect the acetylcholine-stimulated response. Such probe-dependent effects are diagnostic of an allosteric interaction. In comparison to these effects at M₃, dronedarone is strongly inhibitory toward both pilocarpine and acetylcholine at the M₁ subtype. The effects of dronedarone are consistent with an interaction at the amiodarone site: dronedarone inhibits the enhancement of acetylcholine's response produced by amiodarone at the M₃ subtype; also, NEA reverses the enhancement of pilocarpine's response at M₃ produced by either dronedarone or amiodarone. In studies with the M₁-selective allosteric agonist 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC-260584), amiodarone enhanced the maximal response observed, whereas dronedarone was inhibitory. On the other hand, benzyl quinolone carboxylic acid, the well-known allosteric ligand that dramatically enhances the potency of acetylcholine at the M₁ subtype, had no effect on the response profile of AC-260584. In summary, dronedarone acts at M₁ and M₃ muscarinic receptors in a manner that complements amiodarone and provides an additional tool with which to investigate this novel allosteric site.

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Section: Discussionmentioning

confidence: 99%

Dronedarone Modulates M1 and M3 Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

et al. 2016

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“…24,25,[56][57][58] Since allosteric modulators typically bind to less conserved sites compared to the active site of an enzyme, they may confer greater specificity in kinase regulation. [7][8][9] In 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 …”

Section: Principal Component and Covariance Analysismentioning

confidence: 99%

“…Allosteric modulators typically bind to less conserved sites compared to the active site of an enzyme and thus they may confer greater specificity in kinase regulation. [7][8][9] Selective targeting of the PI3Kα isoform is of particular pharmacological interest since overactivation of PI3Kα signaling is one of the most frequent events leading to cancer. [10][11][12] Deregulation of the PI3Kα pathway may occur by several different mechanisms, including somatic mutations and amplification of genes encoding key components of the PI3Kα pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have recently focused on unveiling allosteric modulation of proteins with small molecules by exploiting novel binding pockets for drug discovery. 8,9,[22][23][24][25][26][27][28][29] Based on such approaches and the study by Hon et al, we aim to gain insights into the design of novel selective inhibitors that bind close to the mutated region of the protein.…”

Section: Introductionmentioning

confidence: 99%

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Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Kα

et al. 2014

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Allosteric modulators offer a novel approach for kinase inhibition because they target less conserved binding sites compared to the active site; thus, higher selectivity may be obtained. PIK-108, a known pan phosphoinositide 3-kinase (PI3K) inhibitor, was recently detected to occupy a non-ATP binding site in the PI3Kα C-lobe. This newly identified pocket is located close to residue 1047, which is frequently mutated in human cancers (H1047R). In order to assess the interactions, stability, and any possible allosteric effects of this inhibitor on PI3Kα, extensive molecular dynamics (MD) simulations in aqueous solution were performed for the wild type (WT) human, WT murine, and H1047R human mutant PI3Kα proteins with PIK-108 placed in both catalytic and non-ATP sites. We verify the existence of the second binding site in the vicinity of the hotspot H1047R PI3Kα mutation through binding site identification and MD simulations. PIK-108 remains stable in both sites in all three variants throughout the course of the simulations. We demonstrate that the pose and interactions of PIK-108 in the catalytic site are similar in the murine WT and human mutant forms, while they are significantly different in the case of human WT PI3Kα protein. PIK-108 binding in the non-ATP pocket also differs significantly among the three variants. Finally, we examine whether the non-ATP binding site is implicated in PI3Kα allostery in terms of its communication with the active site using principal component analysis and perform in vitro experiments to verify our hypotheses.

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“…1–10 Insight into the therapeutic potential of M 5 comes largely from genetic studies in M 5 -KO mice, which exhibit reduced sensitivity to the rewarding effects of cocaine and opiates. 11–13 Recently, an association between an M 5 SNP and an addictive phenotype was observed in man, directly linking M 5 to drug abuse and reward.…”

mentioning

confidence: 99%

Further optimization of the M5 NAM MLPCN probe ML375: Tactics and challenges

Kurata

Gentry

Kokubo

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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This letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.

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2013 Philip S. Portoghese Medicinal Chemistry Lectureship: Drug Discovery Targeting Allosteric Sites

Cited by 28 publications

References 88 publications

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Dronedarone Modulates M<sub>1</sub> and M<sub>3</sub> Muscarinic Receptors with Subtype Selectivity, Functional Selectivity, and Probe Dependence

Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Kα

Further optimization of the M5 NAM MLPCN probe ML375: Tactics and challenges

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