Elucidating the Inhibiting Mode of AHPBA Derivatives against HIV-1 Protease and Building Predictive 3D-QSAR Models
Identifieur interne : 001C36 ( Istex/Curation ); précédent : 001C35; suivant : 001C37Elucidating the Inhibiting Mode of AHPBA Derivatives against HIV-1 Protease and Building Predictive 3D-QSAR Models
Auteurs : Xaioqin Huang [République populaire de Chine] ; Liaosa Xu [République populaire de Chine] ; Xiaomin Luo [République populaire de Chine] ; Kangnian Fan [République populaire de Chine] ; Ruyun Ji [République populaire de Chine] ; Gang Pei [République populaire de Chine] ; Kaixian Chen [République populaire de Chine] ; Hualiang Jiang [République populaire de Chine]Source :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2001.
Abstract
The Lamarckian genetic algorithm of AutoDock 3.0 has been used to dock 27 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acids (AHPBAs) into the active site of HIV-1 protease (HIVPR). The binding mode was demonstrated in the aspects of the inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters (τ1, τ2, and τ3 listed in Table ) and root mean square deviation values as compared with the known inhibitor, kni272, show that both kinds of inhibitors interact with HIVPR in a very similar way. The r2 value of 0.860 indicates that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of AHPBAs were reasonably explored. Using the binding conformations of AHPBAs, consistent and highly predictive 3D-QSAR models were developed by performing CoMFA, CoMSIA, and HQSAR analyses. The reasonable rcorss2 values were 0.613, 0.530, and 0.717 for CoMFA, CoMSIA, and HQSAR models, respectively. The predictive ability of these models was validated by kni272 and a set of nine compounds that were not included in the training set. Mapping these models back to the topology of the active site of HIVPR leads to a better understanding of vital AHPBA−HIVPR interactions. Structural-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel HIVPR inhibitors.
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DOI: 10.1021/jm0102710
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Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Fudan University.</mods:affiliation><wicri:noCountry code="no comma"> Fudan University.</wicri:noCountry></affiliation></author><author><name sortKey="Ji, Ruyun" sort="Ji, Ruyun" uniqKey="Ji R" first="Ruyun" last="Ji">Ruyun Ji</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation><wicri:noCountry code="subField">Sciences.</wicri:noCountry></affiliation></author><author><name sortKey="Pei, Gang" sort="Pei, Gang" uniqKey="Pei G" first="Gang" last="Pei">Gang Pei</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Biochemistry and Cell Biology, ShanghaiInstitutes for Biological Sciences, Chinese Academy of Sciences.</mods:affiliation><wicri:noCountry code="subField">Sciences.</wicri:noCountry></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P., gpei@sibs.ac.cn.</mods:affiliation><country wicri:rule="url">République populaire de Chine</country><wicri:regionArea> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P.</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Kaixian" sort="Chen, Kaixian" uniqKey="Chen K" first="Kaixian" last="Chen">Kaixian Chen</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation><wicri:noCountry code="subField">Sciences.</wicri:noCountry></affiliation></author><author><name sortKey="Jiang, Hualiang" sort="Jiang, Hualiang" uniqKey="Jiang H" first="Hualiang" last="Jiang">Hualiang Jiang</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation><wicri:noCountry code="subField">Sciences.</wicri:noCountry></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P., gpei@sibs.ac.cn.</mods:affiliation><country wicri:rule="url">République populaire de Chine</country><wicri:regionArea> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P.</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:7F4E8EA1FBC49F3DB24BCDE0254B6708FFA6041B</idno><date when="2002" year="2002">2002</date><idno type="doi">10.1021/jm0102710</idno><idno type="url">https://api.istex.fr/ark:/67375/TPS-51T68V2C-W/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001C36</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001C36</idno><idno type="wicri:Area/Istex/Curation">001C36</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Elucidating the Inhibiting Mode of AHPBA Derivatives against HIV-1 Protease
and Building Predictive 3D-QSAR Models</title><author><name sortKey="Huang, Xaioqin" sort="Huang, Xaioqin" uniqKey="Huang X" first="Xaioqin" last="Huang">Xaioqin Huang</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation><affiliation><mods:affiliation> Shanghai Institute of Biochemistry and Cell Biology, ShanghaiInstitutes for Biological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation></author><author><name sortKey="Xu, Liaosa" sort="Xu, Liaosa" uniqKey="Xu L" first="Liaosa" last="Xu">Liaosa Xu</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Fudan University.</mods:affiliation></affiliation></author><author><name sortKey="Luo, Xiaomin" sort="Luo, Xiaomin" uniqKey="Luo X" first="Xiaomin" last="Luo">Xiaomin Luo</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation></author><author><name sortKey="Fan, Kangnian" sort="Fan, Kangnian" uniqKey="Fan K" first="Kangnian" last="Fan">Kangnian Fan</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Fudan University.</mods:affiliation></affiliation></author><author><name sortKey="Ji, Ruyun" sort="Ji, Ruyun" uniqKey="Ji R" first="Ruyun" last="Ji">Ruyun Ji</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation></author><author><name sortKey="Pei, Gang" sort="Pei, Gang" uniqKey="Pei G" first="Gang" last="Pei">Gang Pei</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Biochemistry and Cell Biology, ShanghaiInstitutes for Biological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P., gpei@sibs.ac.cn.</mods:affiliation><country wicri:rule="url">République populaire de Chine</country><wicri:regionArea> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P.</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Kaixian" sort="Chen, Kaixian" uniqKey="Chen K" first="Kaixian" last="Chen">Kaixian Chen</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation></author><author><name sortKey="Jiang, Hualiang" sort="Jiang, Hualiang" uniqKey="Jiang H" first="Hualiang" last="Jiang">Hualiang Jiang</name><affiliation wicri:level="1"><mods:affiliation>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437, People's Republic of China</mods:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Center for Drug Design and Discovery, State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road,Shanghai 200031, People's Republic of China, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200032, People's Republic of China, andDepartment of Chemistry, Fudan University, Shanghai 2000437</wicri:regionArea></affiliation><affiliation><mods:affiliation> Shanghai Institute of Materia Medica, Shanghai Institutes forBiological Sciences, Chinese Academy of Sciences.</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P., gpei@sibs.ac.cn.</mods:affiliation><country wicri:rule="url">République populaire de Chine</country><wicri:regionArea> To whom correspondence should be addressed. Tel: +86-21-64311833 ext. 222. Fax: +86-21-64370269. E-mail: H.J., hljiang@mail.shcnc.ac.cn, jiang@iris3.simm.ac.cn; G.P.</wicri:regionArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2001</date><date type="published">2002</date><biblScope unit="vol">45</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="333">333</biblScope><biblScope unit="page" to="343">343</biblScope></imprint><idno type="ISSN">0022-2623</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The Lamarckian genetic algorithm of AutoDock 3.0 has been used to dock 27 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acids (AHPBAs) into the active site of HIV-1 protease (HIVPR). The binding mode was demonstrated in the aspects of the inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters (τ1, τ2, and τ3 listed in Table ) and root mean square deviation values as compared with the known inhibitor, kni272, show that both kinds of inhibitors interact with HIVPR in a very similar way. The r2 value of 0.860 indicates that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of AHPBAs were reasonably explored. Using the binding conformations of AHPBAs, consistent and highly predictive 3D-QSAR models were developed by performing CoMFA, CoMSIA, and HQSAR analyses. The reasonable rcorss2 values were 0.613, 0.530, and 0.717 for CoMFA, CoMSIA, and HQSAR models, respectively. The predictive ability of these models was validated by kni272 and a set of nine compounds that were not included in the training set. Mapping these models back to the topology of the active site of HIVPR leads to a better understanding of vital AHPBA−HIVPR interactions. Structural-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel HIVPR inhibitors.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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