Development of New Potential Inhibitors of β1 Integrins through In Silico Methods—Screening and Computational Validation

Abstract

Integrins are transmembrane receptors that play a critical role in many biological processes which can be therapeutically modulated using integrin blockers, such as peptidomimetic ligands. This work aimed to develop new potential β1 integrin antagonists using modeled receptors based on the aligned crystallographic structures and docked with three lead compounds (BIO1211, BIO5192, and TCS2314), widely known as α4β1 antagonists. Lead-compound complex optimization was performed by keeping intact the carboxylate moiety of the ligand, adding substituents in two other regions of the molecule to increase the affinity with the target. Additionally, pharmacokinetic predictions were performed for the ten best ligands generated, with the lowest docking interaction energy obtained for α4β1 and BIO5192. Results revealed an essential salt bridge between the BIO5192 carboxylate group and the Mg2+ MIDAS ion of the integrin. We then generated more than 200 new BIO5192 derivatives, some with a greater predicted affinity to α4β1. Furthermore, the significance of retaining the pyrrolidine core of the ligand and increasing the therapeutic potential of the new compounds is emphasized. Finally, one novel molecule (1592) was identified as a potential drug candidate, with appropriate pharmacokinetic profiles, similar dynamic behavior at the integrin interaction site compared with BIO5192, and a higher predicted affinity to VLA-4.

Design and Pharmacological Characterization of α4β1 Integrin Cyclopeptide Agonists: Computational Investigation of Ligand Determinants for Agonism versus Antagonism

“…Very recently, da Silva et al docked BIO1211 into a homology model of the α 4 β 1 integrin. These authors predicted the interaction of AspCOO – with the divalent cation in MIDAS . In the calculated pose, the peptide adopts a reverse S-shape, spanning across the interface between the α 4 and β 1 subunits.…”

“…These authors predicted the interaction of AspCOO − with the divalent cation in MIDAS. 61 In the calculated pose, the peptide adopts a reverse S-shape, spanning across the interface between the α 4 and β 1 subunits. The C-terminal Pro is positioned on top of the groove, while the N-terminal MPUPA is allocated within the lower side of the α/β groove, as observed for the CPPs.…”

Conjecturing about Small-Molecule Agonists and Antagonists of α4β1 Integrin: From Mechanistic Insight to Potential Therapeutic Applications

“…The bioactive conformation of 2 can be compared to that obtained by da-Silva et al for MPUPA-LDVP (BIO1211, Figure 3) using a homology model of α4β1 integrin [94]. In the calculated pose, the ligand's backbone folds in a reverse S-shape, and AspCOO − of the peptide makes a salt bridge with Mg 2+ at MIDAS.…”

“…Frequently, simulations with α4β1 models have been conducted for in silico screening to select potential inhibitors of the same integrin [93,94] or other β1 integrins [95]. For instance, molecular docking was used to assist in the design of a blocking polypeptide (antifibrotic 38-amino-acid polypeptide, AF38Pep) for specific inhibition of extra domain A-FN associations with the fibroblast-expressed α4 integrins [96].…”

“…[57], BIO1211 as reported in Ref. [94], and the agonist THI001 [54]. A-E, U, L refer to binding sites subpockets as shown in Figure 10.…”