Discovery of Potential Chemical Probe as Inhibitors of CXCL12 Using Ligand-Based Virtual Screening and Molecular Dynamic Simulation

Abstract

CXCL12 are small pro-inflammatory chemo-attractant cytokines that bind to a specific receptor CXCR4 with a role in angiogenesis, tumor progression, metastasis, and cell survival. Globally, cancer metastasis is a major cause of morbidity and mortality. In this study, we targeted CXCL12 rather than the chemokine receptor (CXCR4) because most of the drugs failed in clinical trials due to unmanageable toxicities. Until now, no FDA approved medication has been available against CXCL12. Therefore, we aimed to find new inhibitors for CXCL12 through virtual screening followed by molecular dynamics simulation. For virtual screening, active compounds against CXCL12 were taken as potent inhibitors and utilized in the generation of a pharmacophore model, followed by validation against different datasets. Ligand based virtual screening was performed on the ChEMBL and in-house databases, which resulted in successive elimination through the steps of pharmacophore-based and score-based screenings, and finally, sixteen compounds of various interactions with significant crucial amino acid residues were selected as virtual hits. Furthermore, the binding mode of these compounds were refined through molecular dynamic simulations. Moreover, the stability of protein complexes, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and radius of gyration were analyzed, which led to the identification of three potent inhibitors of CXCL12 that may be pursued in the drug discovery process against cancer metastasis.

Can polyoxometalates (POMs) prevent of coronavirus 2019-nCoV cell entry? Interaction of POMs with TMPRSS2 and spike receptor domain complexed with ACE2 (ACE2-RBD): Virtual screening approaches

“…During simulation, a slight enhancement in the Rg value of the 6LZG-POM complex was observed, indicating its structural integrity. The MD simulation results entirely support that POM forms stable complexes with 2OQ5 and 6LZG, indicating its inhibitory properties for the TMPRSS2 and ACE2-RBD receptor, respectively [ 60 ].

Fig.

…”

Revolutionizing antiretroviral therapy for human immunodeficiency virus/AIDS: A computational approach using molecular docking, virtual screening, and 3D pharmacophore building to address therapeutic failure and propose highly effective candidates

“…The 3D pharmacophore model includes five primary common features, each of which represents: F1 = Don: Represents a donor group capable of donating hydrogen bonds during the drug-target interaction, 34 F2 = Acc: Denotes an acceptor group that can form hydrogen bonds with the target protein, 37 F3 = Aro: Signifies an aromatic ring, which often plays a crucial role in hydrophobic interactions and π-π stacking with the target protein, F4 = Aro: Another aromatic ring feature, emphasizing the significance of additional hydrophobic interactions in the drug-target binding, and F5 = Aro: The third aromatic ring feature, further highlighting the importance of multiple aromatic interactions in the pharmacophore model. 38 These five common features combine the essential aspects identified earlier during the pharmacophore model creation.…”

6′-O-Caffeoylarbutin from Quezui Tea: A Highly Effective and Safe Tyrosinase Inhibitor

“…Root mean square fluctuation (RMSF) measures the magnitude of atomic deviations relative to their average positions, indicating the flexibility and local motion characteristics of the system [26]. From Figure 6B, it can be observed that, among the 392 amino acid residues, the mTyr protein exhibits higher RMSF values mainly in the peptide chain region of 240-300, indicating higher flexibility in that area.…”