Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity
Microtubules (MT) are cytoskeletal polymers of αβ-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encour...
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creator | Zúñiga-Bustos, Matías Vásquez, Pilar A Jaña, Gonzalo A Guzmán, José L Alderete, Joel B Jiménez, Verónica A |
description | Microtubules (MT) are cytoskeletal polymers of αβ-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encourages the search for novel MT binding agents with chemically diverse structures and different interaction profiles compared to known active compounds. This work reports the rational discovery of seven novel MT stabilizers using a combination of molecular modeling methods and in vitro experimental assays. Virtual screening, similarity filtering, and molecular mechanics generalized Born surface area (MM/GBSA) binding free energy refinement were employed to select seven potential candidates with high predicted affinity toward the non-taxoid site for MT stabilizers on β-tubulin. MD simulations of 150 ns on reduced MT models suggest that candidate compounds strengthen the longitudinal interactions between tubulin dimers across protofilaments, which is a primary molecular mechanism of action for known MT stabilizers.
MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 μM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents. |
doi_str_mv | 10.1021/acs.jcim.9b01133 |
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MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 μM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents.</description><identifier>ISSN: 1549-9596</identifier><identifier>EISSN: 1549-960X</identifier><identifier>DOI: 10.1021/acs.jcim.9b01133</identifier><identifier>PMID: 32286822</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Assaying ; Binders (materials) ; Binding ; Computer simulation ; Dimers ; Free energy ; In vitro methods and tests ; Modelling ; Optimization ; Polymerization ; Side effects ; Stabilizers (agents) ; Taxol</subject><ispartof>Journal of chemical information and modeling, 2020-06, Vol.60 (6), p.3204-3213</ispartof><rights>Copyright American Chemical Society Jun 22, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c327t-20466ea0b255ddea814f325a6500940abbb65dad17bef4934a6c202f02ae46723</citedby><cites>FETCH-LOGICAL-c327t-20466ea0b255ddea814f325a6500940abbb65dad17bef4934a6c202f02ae46723</cites><orcidid>0000-0001-7337-2946 ; 0000-0002-6783-5657</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,2766,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32286822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zúñiga-Bustos, Matías</creatorcontrib><creatorcontrib>Vásquez, Pilar A</creatorcontrib><creatorcontrib>Jaña, Gonzalo A</creatorcontrib><creatorcontrib>Guzmán, José L</creatorcontrib><creatorcontrib>Alderete, Joel B</creatorcontrib><creatorcontrib>Jiménez, Verónica A</creatorcontrib><title>Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity</title><title>Journal of chemical information and modeling</title><addtitle>J Chem Inf Model</addtitle><description>Microtubules (MT) are cytoskeletal polymers of αβ-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encourages the search for novel MT binding agents with chemically diverse structures and different interaction profiles compared to known active compounds. This work reports the rational discovery of seven novel MT stabilizers using a combination of molecular modeling methods and in vitro experimental assays. Virtual screening, similarity filtering, and molecular mechanics generalized Born surface area (MM/GBSA) binding free energy refinement were employed to select seven potential candidates with high predicted affinity toward the non-taxoid site for MT stabilizers on β-tubulin. MD simulations of 150 ns on reduced MT models suggest that candidate compounds strengthen the longitudinal interactions between tubulin dimers across protofilaments, which is a primary molecular mechanism of action for known MT stabilizers.
MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 μM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents.</description><subject>Assaying</subject><subject>Binders (materials)</subject><subject>Binding</subject><subject>Computer simulation</subject><subject>Dimers</subject><subject>Free energy</subject><subject>In vitro methods and tests</subject><subject>Modelling</subject><subject>Optimization</subject><subject>Polymerization</subject><subject>Side effects</subject><subject>Stabilizers (agents)</subject><subject>Taxol</subject><issn>1549-9596</issn><issn>1549-960X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNo9kMlOwzAURS0EYt6zQpZYpzwPcZtlKWWQCkhMYhc9Jw51lcQldgrlA_huArSs7luce6V3CDli0GPA2SlmvjfLbNVLNDAmxAbZZbFMokTBy-b6jhO1Q_a8nwEIkSi-TXYE5wM14HyXfN2YbIq19VV0ht7k9B6DdTWW9Nz6zC1Ms6RY5_S6ps82NI6OF1i2vwx1Bb3tiJLe2KxxodVtaehDQG1L-2nrVzp8NXXw9N2GaUfW0SN-uDIauWpugg12Yegw68KG5QHZKrD05nCV--TpYvw4uoomd5fXo-EkygTvh4iDVMogaB7HeW5wwGQheIwqBkgkoNZaxTnmrK9NIRMhUWUceAEcjVR9LvbJyd_uvHFvrfEhnbm26d71KZesDwBKDjoK_qjuLe8bU6TzxlbYLFMG6Y_4tBOf_ohPV-K7yvFquNWVyf8La9PiG8h2gmQ</recordid><startdate>20200622</startdate><enddate>20200622</enddate><creator>Zúñiga-Bustos, Matías</creator><creator>Vásquez, Pilar A</creator><creator>Jaña, Gonzalo A</creator><creator>Guzmán, José L</creator><creator>Alderete, Joel B</creator><creator>Jiménez, Verónica A</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SC</scope><scope>7SR</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>JQ2</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><orcidid>https://orcid.org/0000-0001-7337-2946</orcidid><orcidid>https://orcid.org/0000-0002-6783-5657</orcidid></search><sort><creationdate>20200622</creationdate><title>Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity</title><author>Zúñiga-Bustos, Matías ; Vásquez, Pilar A ; Jaña, Gonzalo A ; Guzmán, José L ; Alderete, Joel B ; Jiménez, Verónica A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c327t-20466ea0b255ddea814f325a6500940abbb65dad17bef4934a6c202f02ae46723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Assaying</topic><topic>Binders (materials)</topic><topic>Binding</topic><topic>Computer simulation</topic><topic>Dimers</topic><topic>Free energy</topic><topic>In vitro methods and tests</topic><topic>Modelling</topic><topic>Optimization</topic><topic>Polymerization</topic><topic>Side effects</topic><topic>Stabilizers (agents)</topic><topic>Taxol</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zúñiga-Bustos, Matías</creatorcontrib><creatorcontrib>Vásquez, Pilar A</creatorcontrib><creatorcontrib>Jaña, Gonzalo A</creatorcontrib><creatorcontrib>Guzmán, José L</creatorcontrib><creatorcontrib>Alderete, Joel B</creatorcontrib><creatorcontrib>Jiménez, Verónica A</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Computer and Information Systems Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><jtitle>Journal of chemical information and modeling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zúñiga-Bustos, Matías</au><au>Vásquez, Pilar A</au><au>Jaña, Gonzalo A</au><au>Guzmán, José L</au><au>Alderete, Joel B</au><au>Jiménez, Verónica A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity</atitle><jtitle>Journal of chemical information and modeling</jtitle><addtitle>J Chem Inf Model</addtitle><date>2020-06-22</date><risdate>2020</risdate><volume>60</volume><issue>6</issue><spage>3204</spage><epage>3213</epage><pages>3204-3213</pages><issn>1549-9596</issn><eissn>1549-960X</eissn><abstract>Microtubules (MT) are cytoskeletal polymers of αβ-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encourages the search for novel MT binding agents with chemically diverse structures and different interaction profiles compared to known active compounds. This work reports the rational discovery of seven novel MT stabilizers using a combination of molecular modeling methods and in vitro experimental assays. Virtual screening, similarity filtering, and molecular mechanics generalized Born surface area (MM/GBSA) binding free energy refinement were employed to select seven potential candidates with high predicted affinity toward the non-taxoid site for MT stabilizers on β-tubulin. MD simulations of 150 ns on reduced MT models suggest that candidate compounds strengthen the longitudinal interactions between tubulin dimers across protofilaments, which is a primary molecular mechanism of action for known MT stabilizers.
MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 μM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32286822</pmid><doi>10.1021/acs.jcim.9b01133</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-7337-2946</orcidid><orcidid>https://orcid.org/0000-0002-6783-5657</orcidid></addata></record> |
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subjects | Assaying Binders (materials) Binding Computer simulation Dimers Free energy In vitro methods and tests Modelling Optimization Polymerization Side effects Stabilizers (agents) Taxol |
title | Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity |
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