Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • Moving forward to series the energy minimized conformation

    2021-11-30

    Moving forward to series , the energy minimized conformation of Sennoside C synthesis within the binding pocket is quite interesting. The indole-based tail guides the TZD head for a highly-favored interaction with all residues of the H-bonding triad (). In addition, an extra bonding with H449 in the AF-2 helix was achieved. Such preferential settling furnished the highest docking score () among this series which was interpreted through the significantly improved result. Compounds and , the second in rank, were accommodated in the hydrophobic arm (II) showing π-stacking with F226, H-bonding between the linker oxygen and R288, and hydrophobic interactions with L228, L333 and P227. Such accommodations drag and deeper into the hydrophobic pocket anchoring the TZD far from the triad with only a single interaction with Y473 (c). We then turned our attention to the proposed docking poses in hFFAR1. All our ligands were predicted to occupy the allosteric binding site rather than the canonical orthosteric site. In a similar fashion to the crystallized fasiglifam, the proposed docking modes force the hydrophobic tails to extend out through the space between TM3 and TM4 of the hFFAR1 receptor. Both the hydrophobic and steric interactions along the hydrophobic tails influence the anchoring of the ligands’ polar heads with the arginine-tyrosine polar network. The edge-on π-π interaction of W174 or π-stacking of F142 and the respective ligand’s central aromatic ring, orient the TZD head for a proper H bonding with the crucial arginines. In the benzhydrol-based series (), one of the aromatic rings shows good overlapping with fasiglifam’s terminal phenyl groups, while the other points deeper into the lipid membrane layer. In addition to these hydrophobic interactions, the terminal methoxy in shows upward direction forming an H-bond with P80 (a). Actually, H-bonding groups on the hydrophobic tails play a crucial role in ligand binding in this series. This is obvious when comparing the activities of and to those of and . On the contrary, steric clashes with L158 and P80 with the methyl of the inactive caused a marked deterioration of the activity. As expected, series show extensive complex charge networks with the critical arginine residues of FFAR1 (). This was in advent for our later series keeping their EC down to one digit micromolar potencies. Compounds , and , the front-runner representatives of series , showed great overlapping with the crystallized fasiglifam. Their leading compound displayed favorable π-π interaction with F142 and W174. Moreover, its hydrophobic tail expressed interaction with L135, L138, L158, P80, F142, V81 and V84, similar to fasiglifam’s biphenyl scaffold. These favored tail housing, furnish minimal clashes with TM3 and TM4 residues. In addition, it ensures the desired TZD anchoring guided by perfect π-π interaction with F87 (b). On the other hand, the large and rigid phenyl substituent in the inactive compound is particularly prone to steric clashes with V81, P80 and F142. In case of , the longer linker together with structural rigidity of its naphthyl moiety shift the TZD little far from R183 while force the central aromaticity to be in a vertical plane disrupting its π-π stacking with F142 and lose the H-bonding with Y91 (). Interestingly, compound showed unfamiliar orientation in which the TZD head was inverted bringing its 2ry nitrogen too close to R258 side chain nitrogen prone to steric clashes rather than H-bonding (). Moreover, such anchoring prevents the desirable H-bonding interaction with Y91. This binding mode could be forced by the free hydroxyl group on benzimidazole scaffold. It is believed that etherification of such hydroxy group with alkyl sulphone analogues as in fasiglifam, would bring the TZD to a more favored orientation with the sulphone directed upwards., The encouraging agonistic activities were anticipated to translate well into an efficacy. We decided to scrutinize compounds , , , and using blood glucose and plasma triglycerides (TG) testing. Rosiglitazone, a well-recognized PPAR-γ full agonist, was used as our positive control for its capability to lower both the circulating glucose and TG levels. On the other hand, selection of these four compounds was rationalized by their high potencies and diverse chemical structures.