Pharmacophore Definition and Three-Dimensional Quantitative Structure-Activity Relationship Study on Structurally Diverse Prostacyclin Receptor Agonists

Abstract

Prostacyclin is an endogenous mediator that shows potent platelet inhibitory activity and powerful relaxation of peripheral resistance vessels. Prostacyclin receptor agonists are valuable drugs in the treatment of various vascular diseases spanning primary pulmonary hypertension to Raynaud's syndrome. Although agonists from various structural classes were synthesized, a common pharmacophore was never defined. Therefore, an attempt was made to integrate the different agonists into a single model. A dataset of structurally diverse prostacyclin receptor agonists was tested for its affinity to the human platelet prostacyclin receptor. The dataset included prostanoid and nonprostanoid ligands comprising iloprost, cicaprost, and BMY45778. Extensive conformational analyses were performed for both classes of compounds because of the absence of rigid templates. The search and superimposition procedure yielded a pharmacophore that aligns the essential carboxylate group of the agonists as well as demonstrates that different functional groups in prostanoid and nonprostanoid agonists can be arranged in a uniform conformation. A three-dimensional quantitative structure-activity relationship study was performed using the programs GRID and GOLPE. This analysis yielded a cross-validated correlation coefficient of 0.77. With this model, it is possible to predict the affinity of untested compounds.Prostacyclin (PGI 2 ), an endogenous mediator, is synthesized primarily in the vascular endothelium. It plays an important role in the regulation of blood flow; it is a potent vasodilator and inhibits platelet aggregation. Both actions are mediated by a specific G-protein coupled receptor, the prostacyclin receptor (IP receptor). The binding of PGI 2 to this receptor leads to the coupling of G s protein to adenylate cyclase and subsequent elevation of intracellular cAMP levels.PGI 2 is a clinically useful agent for the precise control of platelet function. Its use is impaired by its instability: the enol ether linkage of PGI 2 is spontaneously hydrolyzed with a half-life of 3 min (Stehle, 1982;Armstrong, 1996), limiting therapeutic application to parenteral administration. Much effort was therefore directed toward developing metabolically stable and orally available IP-receptor agonists. These can be divided into two groups: the so-called prostanoid agonists preserve the characteristic structural features found in PGI 2 , namely the carboxylate group and hydroxyl functions at C-9 and C-15 (see Fig. 1), whereas the nonprostanoid agonists do not show any structural similarities with PGI 2 except for the essential carboxylate group. As can be seen in Fig. 2, the skeletons of the nonprostanoid IP receptor agonists differ considerably. In some compounds, putative hydrogen bond acceptors such as heterocycles (i.e., oxazole) or oxime groups serve instead of the hydroxyl groups.Several groups have previously attempted to define a pharmacophore for prostacyclin receptor agonists (Tsai et al., 1991; Meanwell et al., 1993a,b), and structure...

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

“…In this method, one compound is omitted during the generation of a new pharmacophore model, and its affinity is predicted by that new model. The model building and estimation cycle is repeated until each compound is omitted once [33] . This test verifies whether the correlation coefficient of the training-set compounds depends mainly on one particular compound [34] .…”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…Although the OH groups at C11 and C15 in prostanoid IP agonists facilitate hydrogen bonding to PRs, heterocyclic nitrogen, oxime nitrogen, or ester groups serve this function in nonprostanoid agonists. Prostanoid IP agonists have higher affinity over nonprostanoid agonists, largely because of their ability to form an additional hydrogen bond to IP receptor (Stoll et al, 2002). Nonprostanoid compounds could have partial or dual IP agonist, …”

“…TXA 2 /TP antagonist, or TXAS inhibitor activity (Stoll et al, 2002;Arehart et al, 2007) (Table 3). Commonly used IP analogs in clinical trials include epoprostenol, iloprost, carbacyclin, cicaprost, beraprost, and treprostinil (Tanaka et al, 2004) (Fig.…”

Allosteric Site on Muscarinic Acetylcholine Receptors: Identification of Two Amino Acids in the Muscarinic M2Receptor That Account Entirely for the M2/M5Subtype Selectivities of Some Structurally Diverse Allosteric Ligands inN-Methylscopolamine-Occupied Receptors

“…In the next step, the large cavity, which was found, was investigated using different GRID-probes, imitating the functional groups present in the ligands. Subsequently, the allosteric modulators were manually docked into this cavity according to the favorable positions detected by GRID (Stoll et al, 2002). The two resulting wild-type complexes (diallylcaracurine V ϩ NMS, W84 ϩ NMS) were virtually mutated (M 2 -Tyr 177 3Gln, M 2 -Thr 423 3His, M 2 -Tyr 177 3Gln ϩ Thr 423 3His), and all newly generated complexes were minimized to obtain energetically acceptable geometries.…”