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The Rationale for Targeting the NAD/NADH Cofactor Binding Site of Parasitic S-Adenosyl-L-homocysteine Hydrolase for the Design of Anti-parasitic Drugs
Cai, Sumin Li, Qing-Shan Fang, Jianwen Borchardt, Ronald T. Kuczera, Krzysztof Middaugh, C. Russell Schowen, Richard L.
Cai, Sumin
Li, Qing-Shan
Fang, Jianwen
Borchardt, Ronald T.
Kuczera, Krzysztof
Middaugh, C. Russell
Schowen, Richard L.
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Abstract
Trypanosomal S-adenoyl-L-homocysteine hydrolase (Tc-SAHH), considered as a target for treatment of Chagas disease, has the same catalytic mechanism as human SAHH (Hs-SAHH) and both enzymes have very similar X-ray structures. Efforts toward the design of selective inhibitors against Tc-SAHH targeting the substrate binding site have not to date shown any significant promise. Systematic kinetic and thermodynamic studies on association and dissociation of cofactor NAD/H for Tc-SAHH and Hs-SAHH provide a rationale for the design of anti-parasitic drugs directed toward cofactor-binding sites. Analogues of NAD and their reduced forms show significant selective inactivation of Tc-SAHH, confirming that this design approach is rational.
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This is an Accepted Manuscript of an article published by Taylor & Francis in Nucleosides, Nucleotides and Nucleic Acids in May 2009, available online: http://www.tandfonline.com/10.1080/15257770903051031.
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2009-05
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Taylor & Francis
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Cai, S., Li, Q.-S., Fang, J., Borchardt, R. T., Kuczera, K., Middaugh, C. R., & Schowen, R. L. (2009). The Rationale for Targeting the NAD/NADH Cofactor Binding Site of Parasitic S-Adenosyl-L-homocysteine Hydrolase for the Design of Anti-parasitic Drugs. Nucleosides, Nucleotides & Nucleic Acids, 28(5), 485–503. http://doi.org/10.1080/15257770903051031