Derivatization Design Of Azacyclic Carboxamide-like MAO-B Inhibitors And Construction Of HerbiPAD, A Pesticide-like Assay Method

Parkinson's disease(PD)is one of the most common age-related neurodegenerative diseases.Its pathogenesis is mainly related to the loss of dopamine(DA).Inhibition of monoamine oxidase B(MAO-B),which is mainly present in glial cells of the brain,can lead to elevated DA levels in patients.MAO-B inhibitors have been widely used in PD patients.However,the nonselective irreversible inhibition of MAOs could lead to the accumulation of tyramine and is associated with a serious hypertensive crisis called the “cheese effect” triggered by the consumption of tyramine-rich food.In this study,we previously designed a computational strategy to rapidly detect the selective MAO-B inhibitor(S)-1-(4-(3-fluorophenoxy)benzyl)azacyclobutane-2-formamide(C3).In vitro biological evaluation results showed that C3 molecule is more selective than salfenamide,and is a promising drug for the regulation of MAO-B protein.Therefore,a series of C3 derivatives were derived and designed by auto in silico ligand directing evolution(AILDE)in this study.We analyzed the relationship between the structure and activity of these derivatives,its binding mode with MAO-B receptor protein,and pridicting the drug-likeness and pharmacokinetics of these derivatives.In addition,during the investigation of drug-likeness prediction tools,we found that a number assays tools of agrochemcal-likeness have been developed to screen for potential lead compounds.However,there is currently a lack of user-friendly,comprehensive tools for evaluating the herbicide-likeness of herbicides.Through an integrated analysis incorporating the physicochemical properties of commercial herbicides,a qualitative rule,and three quantitative scoring functions developed for evaluating herbicide-likeness.Herbi PAD is a free web platform integrated with the collected database and scoring function.It contains 542 approved herbicides and more than 29,000 physicochemical descriptors,with an accuracy of 84.2% in distinguishing known herbicides from non-herbicides.The website can be accessed at the following address: http://agroda.gzu.edu.cn:9999/ccb/database/Herbi PAD/.In conclusion,using the AILDE substituent optimization method to design the derivatization of MAO-B inhibitor C3 molecules,it will be possible to find new molecules with better activity than C3 molecules.We developed the herbicide-like evaluation tool Herbi PAD to comprehensively analyze the possibility of any molecule becoming a herbicide,which can help herbicide researchers screen for herbicidal and reduce R&D risks and improve R&D efficiency.