A Molecular Docking of New 9β-Halogenated Prostaglandin Analogs with an Ester Group at C-6 Atom of the α-Side Chain

Abstract

Prostaglandins with cytoprotective activity were studied for a long time and a few PGE1 and PGE2 stable analogs were promoted as drugs: arbaprostil, enprostil, misoprostol and rioptostol. Nocloprost, a 9β-chlorine prostaglandin analog, has been also promoted as a cytoprotective drug; the succes with this compound stimulated the reserches, and many 9β- or 11β-substituted prostaglandins were synthesized and studied for their biological activity. In the same dirrection we previously synthesized new 9β-halogenated prostaglandins having also an ester group at the carbon atom 6. These compounds were now used in a molecular docking study to predict their potential cytoprotective (anti-ulcer) activity. The study has been done with CLC Drug Discovery Workbench 2.4. software and an oxidoreductase enzyme receptor, chosen from the Protein Data Bank, ID: 4KEW. Two recognized drugs, omeprazole (co-crystallized with the enzyme) and nocloprost were used as standard in the study. The 9β-halogenated prostaglandin analogs were finally docked. Nocloprost and all 9β-halogenated compounds had docking score greater than that of omeprazole. The majority of the 9β-halogenated analogs have a docking score even greater than that of nocloprost, indicating that these compounds could have potential cytoprotective activity. Correlations between docking score and substituents on the prostaglandin skeleton have been done.

Lactones in the Synthesis of Prostaglandins and Prostaglandin Analogs

“…A different option was to use the δ-lactone intermediates 199 , having already the ω-side chain with the 15-keto group, to synthesize new 9β-halogenated prostaglandin analogs 200 – 201 by opening the lactone group with saturated diols ( n = 2 to 5) or 2-butyne-1,4-diol in the presence of an acid catalyst, like TsOH, with or without an inert solvent, as presented in Scheme 46 [ 147 , 148 ].…”

“…All 9β-halogenated compounds and nocloprost with docking scores greater than that of omeprazole. The majority of the 9β-halogenated analogs (12 compounds) have a docking score greater than that of nocloprost, indicating that their cytoprotective (anti-ulcer) activity could be greater than that of nocloprost, which gave an impulse to further study the compounds [ 149 ].…”

A Molecular Docking of New 9β-Halogenated Prostaglandin Analogues

“…Similarly, nocloprost, a 9β-chlorine prostaglandin analogue, and many 9β-and 11βsubstituted prostaglandins were synthesized and studied for their biological activity. In the same direction, we have synthesized 9β-halogenated prostaglandins of types 2 and 3, starting from the δlactone compound 1 with diols (n = 0 to 4) or 2-butyn-1,4-diol, catalyzed by toluenesulfonic acid [1,2] (Scheme 1).…”

“…or HO OH n OH HO 2a, Hlg = Cl, X = Cl, n = 0 2b, Hlg = Cl, X = Cl, n = 1 2c, Hlg = Br, X = Cl, n = 1 2d, Hlg = F, X = Cl, n = 1 2e, Hlg = Cl, X = Cl, n = 2 2f, Hlg = Cl, X = CF 3 , n = 2 2g, Hlg = Br, X = Cl, n = 2 2h, Hlg = F, X = Cl, n = 2 2i, Hlg = Cl, X = Cl, n = 3 2j, Hlg = Cl, X = Cl, n = 4 2k, Hlg = Cl, X = Cl, n = 2, R 1 = OH, R 2 = H 2l, Hlg = Cl, X = CF 3 , n = 2, R 1 =OH R 2 =H 3a, Hlg = Cl, X = Cl, R 1 , R 2 = O 3b, Hlg = Cl, X = CF 3 , R 1 , R 2 = O 3c, Hlg = Cl, X = Cl, R 1 = OH R 2 = H 3d, Hlg = Cl, X = CF 3 , R 1 We completed a molecular docking study, using CLC Drug Discovery Workbench 2.4. software (QIAGEN Bioinformatics, Aarhus, Denmark) and an oxidoreductase enzyme receptor, chosen from the Protein Data Bank, ID: 4KEW (www.rcsb.org), to determine the predicted cytoprotective activity of the new compounds. In the study, we use as a standard two recognized drugs, omeprazole (cocrystallized with the enzyme) and nocloprost.…”