QSAR, design, and molecular docking study of phenoxypyridine derivatives as protoporphyrinogen IX oxidase inhibitors
Hafiz Aji Aziz, Chandra Pratama Putra, Wita Putri Nirwani, Hendrawan

Universitas Pendidikan Indonesia

Abstract

Herbicides are very important used in crop production to protect them from competition with weeds to increase crop yields and quality of crop. The herbicide protoporphyrinogen oxidase (PPO, EC 1.3.3.4) acts on the protoporphyrinogen oxidase enzyme, which catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX. In this study, a series of new phenoxypyridine derivatives were developed as protoporphyrinogen oxidase inhibitors. In this case, QSAR (Quantitative Structure-Activity Relationship) was used to determine the binding mode and its structural stability as a structure of a protoporphyrinogen oxidase inhibitor, to make a protoporphyrinogen oxidase inhibitor based on the synthesized compound. We used 21 data on phenoxypyridine derivatives containing coumarins with activity (IC50) obtained from previous studies and then made logIC50 as homogeneity of research data. The structure was optimized using the AM1 semi-empirical method and calculations were performed using the ORCA software. In modeling the QSAR equation, the BuildQSAR software using the Multiple Linear Regression (MLR) method is used and the equation search algorithm uses a genetic algorithm. The resulting QSAR equation is \[logIC_{50}=7.5121\left(\pm3.3992\right)\left[C17\right]+0.0230\left(\pm0.0074\right)\left[Energy\right]-244.3649\left(\pm87.0787\right)\left[C6\right]+38.4466\left(\pm12.6370\right)\] can be used to calculate the predicted log IC50 value of new compound design. The biological activity of phenoxypyridine derivatives containing coumarins as protoporphyrinogen oxidase inhibitors in the form of log IC50 predicted by the MLR method was QSAR with a value of \[R_{tr}^2=0.820836, Q^2=0.644, F=19.917, R_{val}^2=0.9575, RMSE=0.313593577\] The new phenoxypyridine derivative compound that has the most potential as a protoporphyrinogen oxidase inhibitor with the lowest binding energy value is compound A9 with logIC50 value is -3.66545 and its energy is -7.50 kcal/mole.

Keywords: QSAR, docking, phenoxypyridine, PPO inhibitor

Topic: Theoretical and Computational Chemistry