Fragment hopping approach directed at design of HIV IN-LEDGF/p75 interaction inhibitors

Figures & data

Figure 1  . Chemical structure of derivative CHIBA-3053.

Figure 2.  Chemical structure of derivative CHIBA-3003; Docking pose of derivative CHIBA-3003 (A) superimposed to the pharmacophore model (HBD, magenta; HBA1-HBA2, green; HY1-HY2, cyan; excluded volumes, gray) and (B) into the LEDGF/p75_IBD binding pocket of IN.

Figure 3.  Fragment-based pharmacophore generation.

Figure 4.  Chemical structure of CHIBA-3003 analogues 2c and 3c.

Figure 5.  Glycine (A) and proline (B) fitting the fragment-based pharmacophore. Docking poses of (C) derivative resulting from glycine and (D) derivatives resulting from proline (R and S stereoisomers).

Scheme 1.  Reagents and conditions: (i) HBTU, DIPEA, DMF, Gly or L-Pro, r.t. over-night; (ii) HBTU, DIPEA, DMF, Gly or L-Pro, MW: 80°C, 10 min, 100 W; (iii) BBr₃, N₂, r.t., over-night; (iv) DMF, K₂CO₃, 4-fluorobenzyl bromide or 3,5-dimethylbenzyl bromide, r.t., 1 h.

Table 1.  Inhibition of IN-LEDGF/p75 interaction.

N°	% Inhibition at 100 µM	N°	% Inhibition at 100 µM
2a	NA	5b	NA
2b	26%	5c	34%
2c	19%	6a	25%
3a	NA	6b	34%
3b	NA	6c	34%
3c	NA	7a	NA
4a	NA	7b	39%
4b	NA	7c	NA
4c	21%	CHIBA-3003	71%
5a	NA	CHIBA-3053	94%

NA, not active.