**Investigation of Phospholipase C**γ**1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors**

**Neha Tripathi <sup>1</sup> , Iyanar Vetrivel <sup>1</sup> , Stéphane Téletchéa 2 , Mickaël Jean <sup>3</sup> , Patrick Legembre 3,4 and Adèle D. Laurent 1,\***


Received: 27 August 2019; Accepted: 19 September 2019; Published: 23 September 2019

**Abstract:** The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLCγ1 and its known binding partners. Indeed, molecular modeling of PLCγ1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLCγ1 and a comparable or higher binding affinity to ritonavir (∆Gbind < −25 kcal/mol), one of the most potent inhibitor reported till now.

**Keywords:** phospholipase C gamma 1; SLP76; virtual screening; pharmacophore mapping; molecular docking; molecular dynamics
