Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores)
All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate trans...
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| Veröffentlicht in: | Journal of molecular graphics & modelling 2018-05, Vol.81, p.125-133 |
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| container_title | Journal of molecular graphics & modelling |
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| creator | Shah, Khushbu Raghavan, Sudhir Hou, Zhanjun Matherly, Larry H. Gangjee, Aleem |
| description | All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics. Four-point validated models (pharmacophores) were generated for PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA) based on inhibition (IC50) of proliferation of isogenic Chinese hamster ovary (CHO) cells engineered to express only human PCFT or only RFC. Our results revealed substantial differences in structural features required for transport of novel molecules by these transporters which can be utilized for developing transporter-selective antifolates.
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| doi_str_mv | 10.1016/j.jmgm.2018.02.007 |
| format | Article |
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[Display omitted]</description><subject>Animals</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Drug Development</subject><subject>Folic Acid Antagonists - chemistry</subject><subject>Folic Acid Antagonists - pharmacology</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Structure</subject><subject>Proton-Coupled Folate Transporter - chemistry</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Reduced Folate Carrier Protein - chemistry</subject><subject>Reproducibility of Results</subject><issn>1093-3263</issn><issn>1873-4243</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1q3TAQhUVJadK0L9BF8TJZ2BlbkmVDCYSkTQuBbtq1kKVRri62ZSRdQ96lD1vd3jY_m66kYc75Bs4h5EMNVQ11e7GtttP9VDVQdxU0FYB4RU7qTtCSNYwe5T_0tKRNS4_J2xi3AEA7EG_IcdNzDoKxE_LrBlcc_TLhnAo1m2JVozMqOT8X3hZ6g5PTaiwsqrQLGMtBRTTFEnzyc6n9bhnzaP2oEhYpqDkuPiQMF0ont7r08Aca0Oz0k06rENxzzeQNjrE4WzYqTEr7ZePzrfN35LVVY8T3f99T8vPL5x_XX8u777ffrq_uSs2gTaXRdTdYrTuw7SAYtdwwboXVpkc-KCZ6a3vKh3a_sHmihvO2E2g6YNoaekouD9xlN0xodM4iqFEuwU0qPEivnHy5md1G3vtV8p73QEUGNAeADj7GgPbRW4PcdyW3ct-V3HcloZG5q2z6-Pzqo-VfOVnw6SDI2eCaA5NRO5xzkC6gTtJ49z_-b5irrX0</recordid><startdate>20180501</startdate><enddate>20180501</enddate><creator>Shah, Khushbu</creator><creator>Raghavan, Sudhir</creator><creator>Hou, Zhanjun</creator><creator>Matherly, Larry H.</creator><creator>Gangjee, Aleem</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20180501</creationdate><title>Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores)</title><author>Shah, Khushbu ; Raghavan, Sudhir ; Hou, Zhanjun ; Matherly, Larry H. ; Gangjee, Aleem</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-dc18bfcc80f6b743f5d45f7fcd9e5ba479ff935b6f5d4f79f3d55687ed804cfd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Drug Development</topic><topic>Folic Acid Antagonists - chemistry</topic><topic>Folic Acid Antagonists - pharmacology</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular Structure</topic><topic>Proton-Coupled Folate Transporter - chemistry</topic><topic>Quantitative Structure-Activity Relationship</topic><topic>Reduced Folate Carrier Protein - chemistry</topic><topic>Reproducibility of Results</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shah, Khushbu</creatorcontrib><creatorcontrib>Raghavan, Sudhir</creatorcontrib><creatorcontrib>Hou, Zhanjun</creatorcontrib><creatorcontrib>Matherly, Larry H.</creatorcontrib><creatorcontrib>Gangjee, Aleem</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of molecular graphics & modelling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shah, Khushbu</au><au>Raghavan, Sudhir</au><au>Hou, Zhanjun</au><au>Matherly, Larry H.</au><au>Gangjee, Aleem</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores)</atitle><jtitle>Journal of molecular graphics & modelling</jtitle><addtitle>J Mol Graph Model</addtitle><date>2018-05-01</date><risdate>2018</risdate><volume>81</volume><spage>125</spage><epage>133</epage><pages>125-133</pages><issn>1093-3263</issn><eissn>1873-4243</eissn><abstract>All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics. Four-point validated models (pharmacophores) were generated for PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA) based on inhibition (IC50) of proliferation of isogenic Chinese hamster ovary (CHO) cells engineered to express only human PCFT or only RFC. Our results revealed substantial differences in structural features required for transport of novel molecules by these transporters which can be utilized for developing transporter-selective antifolates.
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals CHO Cells Cricetulus Drug Development Folic Acid Antagonists - chemistry Folic Acid Antagonists - pharmacology Humans Inhibitory Concentration 50 Molecular Docking Simulation Molecular Dynamics Simulation Molecular Structure Proton-Coupled Folate Transporter - chemistry Quantitative Structure-Activity Relationship Reduced Folate Carrier Protein - chemistry Reproducibility of Results |
| title | Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores) |
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