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Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Bottom Line: Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity.Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules.Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

ABSTRACT
Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

No MeSH data available.


Related in: MedlinePlus

Model of tamoxifen binding to Cryptococcus neoformans calmodulin.As described in the materials and methods, a homology model of C. neoformans calmodulin bound to tamoxifen was built based on the structure of the bovine calmodulin-trifluoperazine complex [25]. A. Binding of tamoxifen to the trifluoperazine binding pocket. The numbers are arbitrary indicators of the four regions of the binding pockets described in the text. B. Overlay of tamoxifen with one molecule of trifluoperazine in the binding pocket. C. Overlay of tamoxifen with binding pocket containing both molecules of trifluoperazine.
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pone.0125927.g006: Model of tamoxifen binding to Cryptococcus neoformans calmodulin.As described in the materials and methods, a homology model of C. neoformans calmodulin bound to tamoxifen was built based on the structure of the bovine calmodulin-trifluoperazine complex [25]. A. Binding of tamoxifen to the trifluoperazine binding pocket. The numbers are arbitrary indicators of the four regions of the binding pockets described in the text. B. Overlay of tamoxifen with one molecule of trifluoperazine in the binding pocket. C. Overlay of tamoxifen with binding pocket containing both molecules of trifluoperazine.

Mentions: Tamoxifen was modeled in the CnCam1 binding pocket (Fig 6A) defined as the first two sites occupied during titration of bovine calmodulin with trifluoperazine [25]. The four regions of the tamoxifen molecule interact with four regions of the trifluoperazine-binding pocket as indicated in Fig 6A. The resulting binding models indicate that the B and C rings of tamoxifen occupy the same regions of the binding pocket as the aromatic core of the first trifluoperazine molecule in the bovine calmodulin structure (Fig 6B). Consistent with the trifluoperazine-structure [25], the alkoxy-amino substituent on the aromatic C ring of tamoxifen is positioned analogously to the alkyl-piperazine substituent of trifluoperazine (Fig 6C). As noted by Cook et al. [26], the tethered alkyl-piperazine substituent of trifluoperazine is oriented toward the solvent-exposed region of the binding pocket and appears to interact with a cluster of negatively charged glutamate residues on helices I and IV. Our model indicates that the alkoxy-dimethylamino moiety of tamoxifen interacts with CnCam1 in the same manner (Fig 6A, region 2). Modeling studies of the interaction of tamoxfien with mammalian calmodulin also suggested that the alkylamino group interacts with acidic residues [24]. Consistent with this model, ospemiphene (Fig 2, molecule 9) an analog of toremifene in which the basic alkylamino group has been replaced by a hydroxyl group, is devoid of antifungal activity. Thus, our antifungal activity data and modeling indicate that the requirement for an alkylamino group in this series of compounds is related to interactions with the acidic residues near the binding pocket.


Structure-activity relationships for the antifungal activity of selective estrogen receptor antagonists related to tamoxifen.

Butts A, Martin JA, DiDone L, Bradley EK, Mutz M, Krysan DJ - PLoS ONE (2015)

Model of tamoxifen binding to Cryptococcus neoformans calmodulin.As described in the materials and methods, a homology model of C. neoformans calmodulin bound to tamoxifen was built based on the structure of the bovine calmodulin-trifluoperazine complex [25]. A. Binding of tamoxifen to the trifluoperazine binding pocket. The numbers are arbitrary indicators of the four regions of the binding pockets described in the text. B. Overlay of tamoxifen with one molecule of trifluoperazine in the binding pocket. C. Overlay of tamoxifen with binding pocket containing both molecules of trifluoperazine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446328&req=5

pone.0125927.g006: Model of tamoxifen binding to Cryptococcus neoformans calmodulin.As described in the materials and methods, a homology model of C. neoformans calmodulin bound to tamoxifen was built based on the structure of the bovine calmodulin-trifluoperazine complex [25]. A. Binding of tamoxifen to the trifluoperazine binding pocket. The numbers are arbitrary indicators of the four regions of the binding pockets described in the text. B. Overlay of tamoxifen with one molecule of trifluoperazine in the binding pocket. C. Overlay of tamoxifen with binding pocket containing both molecules of trifluoperazine.
Mentions: Tamoxifen was modeled in the CnCam1 binding pocket (Fig 6A) defined as the first two sites occupied during titration of bovine calmodulin with trifluoperazine [25]. The four regions of the tamoxifen molecule interact with four regions of the trifluoperazine-binding pocket as indicated in Fig 6A. The resulting binding models indicate that the B and C rings of tamoxifen occupy the same regions of the binding pocket as the aromatic core of the first trifluoperazine molecule in the bovine calmodulin structure (Fig 6B). Consistent with the trifluoperazine-structure [25], the alkoxy-amino substituent on the aromatic C ring of tamoxifen is positioned analogously to the alkyl-piperazine substituent of trifluoperazine (Fig 6C). As noted by Cook et al. [26], the tethered alkyl-piperazine substituent of trifluoperazine is oriented toward the solvent-exposed region of the binding pocket and appears to interact with a cluster of negatively charged glutamate residues on helices I and IV. Our model indicates that the alkoxy-dimethylamino moiety of tamoxifen interacts with CnCam1 in the same manner (Fig 6A, region 2). Modeling studies of the interaction of tamoxfien with mammalian calmodulin also suggested that the alkylamino group interacts with acidic residues [24]. Consistent with this model, ospemiphene (Fig 2, molecule 9) an analog of toremifene in which the basic alkylamino group has been replaced by a hydroxyl group, is devoid of antifungal activity. Thus, our antifungal activity data and modeling indicate that the requirement for an alkylamino group in this series of compounds is related to interactions with the acidic residues near the binding pocket.

Bottom Line: Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity.Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules.Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Rochester, Rochester, NY 14642, United States of America.

ABSTRACT
Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold.

No MeSH data available.


Related in: MedlinePlus