Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design

Donati, Greta; D’Amore, Vincenzo Maria; Russomanno, Pasquale; Cerofolini, Linda; Amato, Jussara; Marzano, Simona; Salobehaj, Maria; Rizzo, Domenico; Assoni, Giulia; Carotenuto, Alfonso; Pietra, Valeria La; Seneci, Pierfausto; Fragai, Marco; Brancaccio, Diego; Leva, Francesco Saverio Di; Marinelli, Luciana

doi:10.1016/j.csbj.2023.06.006

Cited by 3 publications

(1 citation statement)

References 81 publications

(158 reference statements)

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“…The affinity of MCL-1 inhibitor A-1210477 was reported as ∼740 nM by MST [13], whereas another study showed 3.5 nM by SPR [14], an over 200-fold difference. More intriguingly, using the same technique for the same interaction produces even larger difference, such as the case between PDL-1 and BMS-202 measured by MST to be 1.1 μM and 37 nM in two different investigations [15, 16]. Therefore, these obviously discrepant data have generated a serious question on the reliability of reported K D values and their associated techniques.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of the Techniques for the Determination of Binding Affinity between a Small Molecule Inhibitor and a Protein Target

Luo,

Chen

2024

Preprint

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The binding affinity constant (K_D) between a small molecule inhibitor and a protein target is pivotal parameter for target identification and early drug discovery. Despite the extensive applications of three major techniques, namely SPR, ITC and MST, the K_D values for a specifically defined binding measured by these techniques are drastically different, which poses a remarkable difficulty to deal with these ambiguous data. Here, we report the evaluation of the accuracy of K_D values from SPR, ITC and MST compared with enzyme kinetics. To enable an objective comparison, we theoretically proved that enzyme competitive inhibition constant (K_i) could directly reflect the binding affinity. Using purine nucleoside phosphorylase, its substrate inosine and competitive inhibitor immucillin-H, we determined respective K_D and K_i values to make a direct comparison. Moreover, we found that the K_D value measured by SPR is more relevant to its K_i value. This study highlights the urgent need on the development of new technologies for the determination of binding affinity between small molecule inhibitors and protein targets.

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Section: Introductionmentioning

confidence: 99%

Comparative Analysis of the Techniques for the Determination of Binding Affinity between a Small Molecule Inhibitor and a Protein Target

Luo,

Chen

2024

Preprint

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A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

Donati,

Viviano,

D'Amore

et al. 2023

Archiv der Pharmazie

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Immunotherapy has emerged as a game‐changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD‐1/PD‐L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole‐containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time‐resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC50) in the submicromolar range and notably, differently from the major part of PD‐L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole‐based compounds as novel promising candidates for PD‐L1 inhibition.

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An updated patent review on PD-1/PD-L1 antagonists (2022-present)

Uzar,

Kaminska,

Rybka

et al. 2024

Expert Opinion on Therapeutic Patents

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Theoretical and experimental studies on the interaction of biphenyl ligands with human and murine PD-L1: Up-to-date clues for drug design

Cited by 3 publications

References 81 publications

Comparative Analysis of the Techniques for the Determination of Binding Affinity between a Small Molecule Inhibitor and a Protein Target

Comparative Analysis of the Techniques for the Determination of Binding Affinity between a Small Molecule Inhibitor and a Protein Target

A combined approach of structure‐based virtual screening and NMR to interrupt the PD‐1/PD‐L1 axis: Biphenyl‐benzimidazole containing compounds as novel PD‐L1 inhibitors

An updated patent review on PD-1/PD-L1 antagonists (2022-present)

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