Design, Virtual Screening, and Synthesis of Antagonists of α_IIbβ₃ as Antiplatelet Agents

Abstract

This article describes design, virtual screening, synthesis, and biological tests of novel αIIbβ3 antagonists, which inhibit platelet aggregation. Two types of αIIbβ3 antagonists were developed: those binding either closed or open form of the protein. At the first step, available experimental data were used to build QSAR models and ligand- and structure-based pharmacophore models and to select the most appropriate tool for ligand-to-protein docking. Virtual screening of publicly available databases (BioinfoDB, ZINC, Enamine data sets) with developed models resulted in no hits. Therefore, small focused libraries for two types of ligands were prepared on the basis of pharmacophore models. Their screening resulted in four potential ligands for open form of αIIbβ3 and four ligands for its closed form followed by their synthesis and in vitro tests. Experimental measurements of affinity for αIIbβ3 and ability to inhibit ADP-induced platelet aggregation (IC50) showed that two designed ligands for the open form 4c and 4d (IC50 = 6.2 nM and 25 nM, respectively) and one for the closed form 12b (IC50 = 11 nM) were more potent than commercial antithrombotic Tirofiban (IC50 = 32 nM).

Ligand-Based Pharmacophore Modeling Using Novel 3D Pharmacophore Signatures

“…Pharmacophore models have proved to be useful for the selection of focused sets of compounds [1,2,3,4]. There are two kinds of pharmacophores: (i) structure-based pharmacophores derived directly from X-ray structures of protein-ligand complexes, and (ii) ligand-based pharmacophores derived from structures of known active compounds.…”

Simplex representation of molecular structure as universal QSAR/QSPR tool

“…4.Why, during the configuration of isomerization, does the enantiomer not always pass through an achiral boundary? Antiviral activity, antimicrobial activity and antitumor activity Pharmacokinetic Parameter [25], [41][42][43][44][45] Affinity for different biological targets [46][47][48][49][50][51][52][53] Different types of toxicity [44], [54][55][56][57][58][59][60][61][62][63][64][65]…”

“…To antagonize the inhibition of platelet aggregation through α IIb β 3 , [ 50 ] detailed the in silico and in vitro testing of QSAR nominated compounds. The consensus screening highlighted three hits against the closed form of the receptor.…”

Emergence of Small-Molecule Non-RGD-Mimetic Inhibitors for RGD Integrins

“…These novel inhibitors were also found to show specificity for their desired integrin over α v β 3 , and no undesired priming of the receptor was observed. In 2015 a second virtual screen of antagonists for α IIb β 3 was reported by Wang et al 60 This work combined the structure-based in silico screen with a ligand-based pharmacophore screen of over 7.3 million Òdrug-likeÓ compounds from the ZINC database. Their campaign identified 11 commercially available compounds, which were obtained and tested for their inhibitory effect against platelet aggregation.…”

“…Their campaign identified 11 commercially available compounds, which were obtained and tested for their inhibitory effect against platelet aggregation. Three compounds were found to exhibit micromolar activity, with compound 13 60 displaying the highest potency, Figure 8. Wang et al also comment that this potential antagonist is predicted to have good solubility, permeability, ADMET properties, and low toxicity in vivo.…”