Targeting MLL2 Protein SET Domain against Non-Hodgkin Lymphoma using Computer-Aided Drug Designing Approach

Abstract

Diffuse large B-cell Lymphoma (DL BCL) is a type of non-Hodgkin lymphoma in adults and is a B-cell cancer. Three common variants were seen morphologically, including anaplastic, centroblastic, and immunoblastic. Mostly, these abnormal cells are centroblastic and appear as medium to large-sized lymphocytes having scanty cytoplasm. The gene, namely KMT2D, also called as MLL2, gives commands for producing lysine-specific methyltransferase 2D enzyme, found in different organs/tissues of the body. When the MLL2 protein is overexpressed then diffuse large B-cell lymphoma occurs. The SET ([Su(var)3-9, Enhancer-of-zeste and Trithorax]) domain of MLL2 protein acts as its active site. Due to aggressiveness, poor prognosis and absence of hormonal therapy, this study focuses on the CADD approach for potential therapeutic drugs to inhibit the activation of the SET Domain of MLL2 Protein as a target protein. 3D structure of SET Domain was retrieved from PDB and inhibitors were obtained through PubChem and Literature. Pharmacophore modelling and virtual screening was performed for identification of novel compounds using LigandScout. AutoDock Vina was used for targeted docking against the predicted active sites of protein to evaluate the potential association of protein and ligands. These interactions were evaluated for binding affinities and DRUGLIKENESS properties using AutoDock Vina, DruLito and Data Warrior respectively. ZINC000014728328(Persicogenin) and ZINC000014727443(Cerasinone) appeared to have least binding energies (-8.4) with high drug likeness(-0.0783 and -0.087682) respectively. Novel selected compounds have improved absorption and better Drug Likeness properties, so it is observed that novel compounds are potent inhibitors having more efficacies and fewer side effects.