Design and In silico Screening of Combinatorial Library of New Herbicidal Analogs of Cycloalka[d]quinazoline-2,4dione−Benzoxazinones Inhibiting Protoporphyrinogen IX Oxidase

Abstract

We virtually design here an important new weedkiller Cycloalka[d]quinazoline-2,4dione−Benzoxazinones (CQB), inhibitors of Protoporphyrinogen IX Oxidase (PPO). Based on computer-assisted combinatorial chemistry techniques, docking, 3D-QSAR and pharmacophore models we first enumerate, focus and in silico screen a virtual library of CQB analogs substituted at positions R1, R2 and R3. By docking inhibitors into the target active site from the crystal structure (PDB ID: 1SEZ) of PPO in complex with a CQB ligand, 3D models of 29 PPO:CQBx complexes with known observed activity (Kiexp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correlation between relative Gibbs free energy (GFE) of receptor-ligand complex formation (ΔΔGcom) and Kiexp: pKiexp = -0.1664 ×ΔΔGcom + 8.306 (1); R2 = 0.94. A 3D QSAR pharmacophore model (PH4) derived from the QSAR directed our effort to design novel CQB analogs. During the design, an initial virtual library of 118 CQB was focused down and PH4 screened to identify 28 promising novel analogs. Their Ki (Kipre) values were predicted by means of equation (1). The most active analog namely CQB22 display Kipre 22 times superior to that of the reported most active training set ligand 17i. Our survey proposes this compounds to the synthesis and to the assessment on herbicidal.