Table 1.
Sequence datasets of gonadotropins and their receptors.
Table 2.
Mutants created for gonadotropins and receptors.
Figure 1.
Flowchart describing the rational design of FSH peptidomimetic (FSHP).
The structures represent information provided in pink boxes.
Table 3.
List of interactions that stabilize the gonadotropin-receptor complexes.
Figure 2.
Binding specificity residues identified for (A) hFSHR-FSH complex and (B) hLHR-LH complex.
The first shell residues are represented by sticks and the second shell residues are represented by ball and stick. The gonadotropins are colored yellow and the receptors are colored green.
Table 4.
Binding specific residues identified for gonadotropin-receptor complexes.
Table 5.
RDOCK energy of the docked complexes.
Figure 3.
Binding modes of MMs02514408 and FSHP_FB predicted by GOLD and Glide.
(A) Opposite binding modes predicted for MMs02514408 with hFSHR (B) Similar binding modes predicted for FSHP_FB with hFSHR. The GOLD and Glide docked poses are shown as blue and pink sticks respectively. hFSHR is depicted in green cartoon representation. (C) Figure illustrating the importance of two planar hydrophobic groups (phenyl rings A and B) present in FSHP_FB (yellow sticks) for hFSHR binding (Molecular surface representation). Ring A forms cation-π interaction with 101R while ring B is embedded in the hydrophobic pocket of the binding site.
Figure 4.
Inter and intra molecular interactions provide rigidity to the spacer connecting rings A and B.
Anionic carboxyl oxygen atom of FSHP_FB (gray sticks) is involved in intramolecular hydrogen bond formation with hydroxyl group present at the ortho-position of Ring A and also forms salt bridge with 104K (orange stick) of hFSHR (green cartoon). The interactions are shown in black dotted lines.
Figure 5.
Chemical structures of the peptidomimetics obtained by in silico structural modifications made at two stereo centers of FSHP_FB viz.
, 11Cα1 and 53Cα3. Substituent groups/atoms are highlighted in blue. FSHP_FB has four structural units viz., L-cysteine (orange), D-phenylalanine (green) and β-alanine (purple).
Table 6.
Docking of peptidomimetics generated during optimisation of FSHP_FB.
Table 7.
Interactions between FSHP and hFSHR in the docked complex.
Figure 6.
MD trajectory analysis of hFSHR-FSHP complex.
(A) Backbone RMSD (B) Total SASAξ (C) Distanceξ and (D) Number of H-bondsξ. ξCalculated between the BSRs of FSHR and FSHP.
Figure 7.
Snapshots of hFSHR-FSHP complex during the course of MD simulation.
(A) The binding mode and interactions of FSHP (green ball and sticks) with hFSHR (cartoon) shown at different time intervals. The hydrogen bonds, electrostatic and cation-π interactions are shown in blue, pink and orange lines respectively. (B) Molecular overlay of FSHP conformations taken at intervals of 1 ns. The conformation of FSHP taken at 0 ns is shown in green sticks. The region of FSHP that displays flexibility during the simulation is circled.
Figure 8.
Analysis of two dihedral angles of FSHP during MD simulation.
The average dihedral angles and probability distributions plotted for (A) 57N-53Cα-52Cβ-45Cγ (B) 25N-21Cα-20Cβ-2Cγ.
Figure 9.
Pharmacophoric similarity of FSHP and hFSHβ.
The chemical space shared by hFSHβ (cyan sticks) and FSHP (green sticks) is color-coded as explained in the side panel. The interactions with the BSRs (orange sticks) of hFSHR (grey cartoon) are shown in black dotted lines. FSHP shares similar pharmacophoric features and molecular interactions with BSRs of hFSHR as hFSHβ.
Figure 10.
Differential binding modes of FSHP to hFSHR and hLHR.
Structures of gonadotropins (yellow cartoon) complexed with their cognate receptors (green cartoon) are super positioned with docked FSHP (pink sticks)-receptor complexes. (A) FSHP binds to hFSHR in a similar mode as that of hFSHβ (B) FSHP binds to hLHR at a site distant from the hLHβ binding site.
Figure 11.
Plot of experimentally determined log IC50 values of 50 compounds versus their Glide scores.
Figure 12.
Docked complexes of hFSHR with (A) Compound 2 (B) Compound 14.
Table 8.
Chemical names of the designed peptidomimetics.