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Novel Dihydrofolate Reductase Inhibitors. Structure-Based versus Diversity-Based Design and High-Throughput Synthesis and Screening. Pierre C. Wyss, Paul Gerber, Peter G. Hartman, Christian Hubschwerlen, Hans Locher, Hans-Peter Marty, Martin Stahl F. Hoffman-La Roche Ltd, Basel Switzerland
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Pierre C. Wyss, Paul Gerber, Peter G. Hartman, Christian Hubschwerlen, Hans Locher, Hans-Peter Marty, Martin Stahl
F. Hoffman-La Roche Ltd, Basel Switzerland
J. Med. Chem. 2003, 46, 2304
- Structure-based library design
- Diversity-based library design
- Inhibit bacterial DHFRs but not human DHFR
- Compound 6 is good practical chemistry, is a key intermediate for library synthesis
- Reactions could be done on 0.35 - 0.7 mM scale
- Purification by HPLC not required
- 1392 compounds made in library format
complexed with S. aureus DHFR
- Diaminopyrimidine is an ideal fit for a narrow pocket in the active site: “needle”
- Docking would be done with the constraint of a fixed position for the needle fragment
- No significant induced fit effects can be observed, assume receptor is rigid for docking experiments
- High similarity at the active site, assume that use of a single crystal structure will be sufficient for screening against all targets
the aminomethyl substituent was not protonated
- Compounds were superimposed in pairs at the newly
formed C-N bond
- The amine substituent was rotated. Conformers with maximum volume
and H-bond-donor and H-bond-acceptor overlap were generated.
- The list of pairwise similarity scores was used for clustering in a binary
tree using a complete linkage algorithm
-- two clusters are combined only if all members of the first are within the distance threshhold of all members of the second
-- Each iteration reduces the number of clusters by one
- Except for compound11, all the compounds were more active against Spn/Sp1
- Only 10 and 13 showed selectivity for bacterial DHFR over Human DHFR
compared to TMP
- The R isomer of 9 helped identify a new cleft in the enzyme