Protein Flexibility and Species Specificity in Structure-Based Drug Discovery: Dihydrofolate Reductase as a Test System

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• 作者：Anna L. Bowman ; Michael G. Lerner ; Heather A. Carlson
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：March 28, 2007
• 年：2007
• 卷：129
• 期：12
• 页码：3634 - 3640
• 全文大小：623K
• 年卷期：v.129,no.12(March 28, 2007)
• ISSN：1520-5126

文摘

In structure-based drug discovery, researchers would like to identify all possible scaffolds for agiven target. However, techniques that push the boundaries of chemical space could lead to many falsepositives or inhibitors that lack specificity for the target. Is it possible to broadly identify the appropriatechemical space for the inhibitors and yet maintain target specificity? To address this question, we haveturned to dihydrofolate reductase (DHFR), a well-studied metabolic enzyme of pharmacological relevance.We have extended our multiple protein structure (MPS) method for receptor-based pharmacophore modelsto use multiple X-ray crystallographic structures. Models were created for DHFR from human andPneumocystis carinii. These models incorporate a fair degree of protein flexibility and are highly selectivefor known DHFR inhibitors over drug-like non-inhibitors. Despite sharing a highly conserved active site,the pharmacophore models reflect subtle differences between the human and P. carinii forms, which identifyspecies-specific, high-affinity inhibitors. We also use structures of DHFR from Candida albicans as a counterexample. The available crystal structures show little flexibility, and the resulting models give poorerperformance in identifying species-specific inhibitors. Therapeutic success for this system may depend onachieving species specificity between the related human host and these key fungal targets. The MPStechnique is a promising advance for structure-based drug discovery for DHFR and other proteins ofbiomedical interest.