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. 2021 Aug 2;64(15):11288–11301. doi: 10.1021/acs.jmedchem.1c00663

Figure 4.

Figure 4

(A) Superimposition of the crystal structure of MTHFD2/15/21 (PDB 7EHM) on MTHFD2/3/21 (PDB 7EHV). For clarity, compound 21 is omitted in the figure. Red dashed lines indicate the hydrogen-bond and green ones indicate the π–π interactions. The tail group of 3 loses the important hydrogen-bond network with MTHFD2 in comparison with 15 and therefore weakens its inhibition toward MTHFD2. (B) and (C) Superimposition of the crystal structure of MTHFD2/15/21 (PDB 7EHM) on MTHFD2/9/21 (PDB 7EHN). (C) is the view of (B) after 60° rotation along the X-axis followed by 35° rotation along the Y-axis. For clarity, compound 21 is omitted in the figure. Red and black dashed lines indicate the hydrogen bond. In (B), the tail group of 9 loses the hydrogen-bond network with MTHFD2 and, instead of direct interactions with Glu141 as observed in 15, the core of 9 forms the hydrogen-bond interaction with Glu141 through a water molecule. In (C), in comparison with 15 (yellow), the indole group of 9 (magenta) forms shape complementarity interactions with MTHFD2 and makes the additional hydrogen-bond interaction with Asn204.