4HOG

Candida glabrata dihydrofolate reductase complexed with NADPH and 5-[3-(2-methoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine (UCP111H)

Summary for 4HOG

• Entry DOI: 10.2210/pdb4hog/pdb
• Related: 3QLR 3QLS 3QLW 4H95 4H96 4H97 4H98 4HOE 4HOF
• Descriptor: Dihydrofolate Reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 5-[3-(2-methoxy-4-phenylphenyl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine, ... (5 entities in total)
• Functional Keywords: antifungal agents, candida glabrata, drug design, enzyme inhibitors, fungal proteins, structure-activity relationship, tetrahydrofolate dehydrogenase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Candida glabrata CBS 138 (yeast)
• Total number of polymer chains: 2
• Total formula weight: 55204.19

Authors

Paulsen, J.L.,Anderson, A.C. (deposition date: 2012-10-22, release date: 2014-03-19, Last modification date: 2023-09-20)

Primary citation

G-Dayanandan, N.,Paulsen, J.L.,Viswanathan, K.,Keshipeddy, S.,Lombardo, M.N.,Zhou, W.,Lamb, K.M.,Sochia, A.E.,Alverson, J.B.,Priestley, N.D.,Wright, D.L.,Anderson, A.C.
Propargyl-Linked Antifolates are Dual Inhibitors of Candida albicans and Candida glabrata.
J.Med.Chem., 57:2643-2656, 2014

PubMed Abstract: Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.

PubMed: 24568657
DOI: 10.1021/jm401916j

Experimental method

X-RAY DIFFRACTION (2 Å)