In Silico Screening and ADME Predictions of Some Quinazolinones as Potential Dihydrofolate Reductase Inhibitors for Anticancer Activity

Abstract

In this paper, in silico screening, conducted before the actual synthesis of some 'best fit' quinazolinone moieties as the possible inhibitors of dihydrofolate reductase enzyme for anticancer activity is reported. Molecular docking of a set of ligands from series of 6,6'-methylenebis- 2-methyl-3-((2/3-aryl)heterocycyl-3/4/5-one)quinazolin-4-(3H)-one (BQ_1-132), 2-alkyl/phenyl-3-(2/3-aryl heterocycyl-3/4/5-one)quinazolin- 4(3H)-one (QHIP_1-132, QHP_1-132, QHM_1-132), 2-phenyl-3-(arylideneamino)- quinazolin-4(3H)-one (QSB_1-31) was performed using Glide® as the docking module. The prediction of absorption, distribution, metabolism and excretion (ADME) properties was obtained with the QikProp® 2.5 module. The 3D ligand-protein complex structure of human dihydrofolate reductase (1BOZ) was obtained from the Protein Database Bank (RCSB PDB) and processed for the docking using the protein preparation wizard module. Methotrexate (MTX) a potent inhibitor of dihydrofolate reductase enzyme was included in test sets, to compare the Glide score (G score) of designed analogues. The binding affinities of different ligands were compared to give E-model score values. Analogues showed comparative G scores with MTX and Raltitrexed.