Design Of Novel Inhibitors Based On Protoporphyrinogen Oxidase

Due to the large population of our country,huge food demand has been produced,which in turn requires continuously increasing food production.The overgrowth of weeds is a serious constraint on food production.For increasing food production,many herbicides are needed to control weeds.Nevertheless,the large application of herbicides leads to the emergence of drug-resistant weeds,which in turn causes the herbicidal effect to be greatly reduced or even completely ineffective.Therefore,it is of great significance to develop a new type of herbicide that is not susceptible to resistance.Protoporphyrinogen oxidase(PPO)inhibitors are herbicides that are less susceptible to resistance.By inhibiting the activity of PPO,the last enzyme in the biosynthesis of chlorophyll,PPO inhibitors can ultimately lead to plant death.PPO inhibitors have the following advantages: low resistance,high selectivity,low effective concentration,wide herbicidal spectrum,and low environmental pollution.Therefore,PPO inhibitors are very potential herbicides.The cycle required to develop a new drug is very long and costly.The use of computer-aided drug design(CADD)can effectively shorten the development cycle of new drugs and greatly reduce the cost of research.When the structure of the receptor protein is known,a receptor-based drug design method can be employed.Molecular docking is a commonly used receptor-based drug design method.There are many commonly used molecular docking software,of which,Auto Dock Vina is the one with high docking accuracy.In computer-aided drug design,the binding energy calculation between protein receptor and drug ligand is a critical step.The Quantum Mechanics(QM)method is a commonly used method for calculating the interaction between a receptor and a ligand,and the calculation result is very accurate.Virtual screening is another important method of computer-aided drug design.By calculating a large number of compound molecules,it is possible to find molecules that bind well to target with known structure.The goal of this study was to design new PPO inhibitors with higher activity in two main aspects.On the one hand,new inhibitor molecules were designed based on the known structure of existing herbicide molecules.Using the calculation model combining Auto Dock Vina and QM,the PPO inhibitors of triazolinones,diphenyl ethers and pyrimidinediones were firstly docked with PPO by Vina,and the binding energies were calculated by QM method.The binding ability of three kinds of inhibitor molecules with PPO was compared and analyzed,and on the basis of their structure,specific substituents were modified,and 18 new PPO inhibitor molecules were designed.The Vina docking and QM binding energies calculations of the newly designed molecules show that the compound P1 has the strongest binding ability with PPO,and its quantum binding energy is as low as-25.79 kcal/mol.So,the compound P1 is a promising new PPO inhibitor.On the other hand,novel PPO inhibitor molecules were designed based on virtual screening technology.From the Drug-Like,Lead-Like and FDA sublibraries in the ZINC database,7495 compounds were selected as the ligands for the virtual screening.The docking of each ligand molecule with the PPO protein model was performed using Auto Dock Vina.The first 20 molecules with the best results were selected in each sublibrary.Then,considering the structure,energy and structural similarity,10 candidate compound molecules in each sublibrary were finally selected,of which,compound 2 of FDA sublibrary has the best docking configuration and binding energy,showing good potential activity.