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Characterization of PD-L1 binding sites by a combined FMO/GRID-DRY approach

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Abstract

The programmed cell death protein 1 (PD-1) and its ligand, PD-L1, constitute an important co-inhibitory immune checkpoint leading to downregulation of immune system. Tumor cells developed a strategy to trigger PD-1/PD-L1 pathway reducing the T cell anticancer activity. Anti-PD-L1 small drugs, generally with improved pharmacokinetic and technological profiles than monoclonal antibodies, became an attractive research topic. Nevertheless, still few works have been published on the chemical features of possible binding sites. In this work, we applied a novel computational protocol based on the combination of the ab initio Fragment Molecular Orbital (FMO) method and a newly developed GRID-DRY approach in order to characterize the PD-L1 binding sites, starting from PD-1/PD-L1 and PD-L1/BMS-ligands (Bristol–Mayers Squibb ligands) complexes. The FMO method allows the calculation of the pair-residues as well as the ligand–residues interactions with ab initio accuracy, whereas the GRID-DRY approach is an effective tool to investigate hydrophobic interactions, not easily detectable by ab initio methods. The present GRID-DRY protocol is able to determine the energy contributions of each ligand atoms to each hydrophobic interaction, both qualitatively and quantitatively. We were also able to identify the three specific hot regions involved in PD-1/PD-L1 protein–protein interaction and in PD-L1/BMS-ligand interactions, in agreement with preceding theoretical/experimental results, and to suggest a specific pharmacophore for PD-L1 inhibitors.

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Abbreviations

BMS:

Bristol–Mayers Squibb

DRY:

Hydrophobic probe

Ees :

Electrostatic energy

Eex :

Exchange repulsion energy

Ect :

Charge transfer energy

Edisp :

Dispersion energy

Esolv :

Solvation energy

EEL:

Electrostatic energy

EHB:

Hydrogen-bonding energy

ELJ:

Lennard–Jones energy

ES:

Entropic energy

FMO:

Fragment molecular orbitals

G:

Region on PD-L1 surface delimited by Asp26, Asp122, Tyr123, Lys124 and Arg125

HE:

Hydrophobic interaction energy

HOP:

Hybrid orbital projection

HTRF:

Homogenous time resolved fluorescence

MAO:

Mechanism of action

MIFs:

Molecular interaction fields

N1:

Neutral flat N–H probe

O:

Carbonyl oxygen probe

OH2:

Water molecule probe

PCM:

Polarizable continuum model

PD-1:

Programmed cell death protein 1

PDB:

Protein data bank

PD-L1:

Programmed cell death protein 1 ligand

PIE:

Pair interaction energy

PIEDA:

Pair interaction energy decomposition analysis

PPI:

Protein–protein interaction

P1:

Region on PD-L1 surface composed of Tyr56, Glu58, Arg113, Met115 and Tyr123

P2:

Region on PD-L1 surface composed of Met115, Ala121 and Ty123

QSAR:

Quantitative structure−activity relationship

R2 :

Squared Pearson’s correlation coefficient

RI-MP2:

Second-order Møller–Plesset perturbation theory (MP2) gradient with resolution of the identity (RI) approximation

3D:

Three-dimensional

SAR:

Structure–activity relationship

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Acknowledgement

We thank the Ministry of Education, University and Research (MIUR) for financial support. Moreover, we are thankful to Prof. Alessandro Marrone for his suggestions and useful discussions.

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Authors and Affiliations

  1. Department of Pharmacy, Università “G. D’Annunzio” Di Chieti-Pescara, Chieti, Italy

    Roberto Paciotti, Mariangela Agamennone, Cecilia Coletti & Loriano Storchi

  2. Molecular Discovery Limited, Middlesex, London, UK

    Loriano Storchi

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  1. Roberto Paciotti
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  2. Mariangela Agamennone
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  4. Loriano Storchi
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Paciotti, R., Agamennone, M., Coletti, C. et al. Characterization of PD-L1 binding sites by a combined FMO/GRID-DRY approach. J Comput Aided Mol Des 34, 897–914 (2020). https://doi.org/10.1007/s10822-020-00306-0

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