Triketoacid inhibitors of HIV-integrase: a new chemotype useful for probing the integrase pharmacophore |
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| Authors: | Walker Michael A Johnson Timothy Ma Zhuping Banville Jacques Remillard Roger Kim Oak Zhang Yunhui Staab Andrew Wong Henry Torri Albert Samanta Himadri Lin Zeyu Deminie Carol Terry Brian Krystal Mark Meanwell Nicholas |
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| Institution: | Department of Medicinal Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb, The Richard L Gelb Center for Pharmaceutical Research and Development, 5 Research Parkway Wallingford, CT 06492, USA. walkerma@bms.com |
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| Abstract: | Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme. |
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