Research On Virtual Screening Of COX-1/2 Ihibitors Of Litsea And The Design And Synthesis Of Anti-HIV Bismethoxy Carbazole Compounds

Inflammation is a pathological phenomenon caused by many factors,and it is an adaptive host response to a variety of physical,chemical and biological stimuli.It is usually beneficial to the body as a defense mechanism against the invasion of foreign substances.Today’s key research areas of inflammation are mainly focused on chronic inflammation,and related diseases include type 2 diabetes,atherosclerosis,asthma,neurodegenerative diseases and so on.These diseases are characterized by great harm to the human body,easy to repeat,and difficult to cure under existing conditions.With the deepening of research,people have observed that cyclooxygenase（COX）is expressed in large amounts in inflamed tissues.COX has two subtypes,cyclooxygenase-1（COX-1）and cyclooxygenase-2（COX-2）.COX-1 is a constitutive isoenzyme,which is expressed in all tissues in the body,while COX-2is generally only expressed in inflamed tissues.COX can process the substrate arachidonic acid（AA）into prostaglandins（PGs）,and PGs is an important inflammatory mediator,which is closely related to the formation of atherosclerosis and arterial thrombosis.People have a long history of using natural plants to treat inflammatory diseases.Among them,Litsea plants are characteristic plants in Yunnan,and their therapeutic effects on inflammatory diseases are widely recorded in medical books.In this work,for the first time,407 natural products reported in the genus Alpinia are the research objects,and cyclooxygenase-1（COX-1）and cyclooxygenase-2（COX-2）are used as targets,through molecular docking.The method studied the binding of these natural products with two cyclooxygenases.As a result,it was found that the apophene-type alkaloids and flavonoids in Litsea generally have good binding ability with the two cyclooxygenases.Therefore,we speculate that these two structural compounds are the effective active ingredients of Litsea anti-inflammatory.We systematically studied the relationship between the 48 apophyllic alkaloids in Litsea and COX-2,and found that the score of apophyllic alkaloids is related to the number of methoxy groups on the molecule.When there is no methoxy group or only one in the case of methoxy groups,the docking score of the molecule is the highest,and when four methoxy groups are included,the score of the molecule is the lowest.In addition,the score is also related to the group connected to the N atom.When N is connected to a hydrogen atom,a methyl group,or a structure that forms a carbon-nitrogen double bond,the score is the highest,and the score is similar.When the acetyl group,allyl group,and ester group are connected,the score becomes very low.It is concluded that reducing the steric hindrance on N is beneficial to the interaction between the molecule and the protein,and increasing the steric hindrance is not conducive to the interaction.In addition,we also studied the relationship between flavonoids and COX-2.We established a quantitative pharmacophore model for COX-2 based on 26 active flavonoids compounds,and used this model to screen three compound databases.Combined with virtual screening methods such as pharmacology,toxicology simulation,molecular docking,de novo evolution,and molecular dynamics simulation,a molecule with a docking score 1.5 times higher than that of the positive drug celecoxib was obtained and named 1-Evo-5.Carbazole compounds have always been a research focus of our research group.In the previous study,several natural carbazole products isolated from Rutaceae plants have been tested and found to have good anti-HIV activity.This result has rarely been reported before,and it is a relatively new research field.In previous studies,we have found that carbazole compounds with a unilateral bismethoxy structure have moderate anti-HIV activity.In order to explain the specific mechanism of carbazole compounds against HIV,we used molecular docking methods to dock carbazole compounds with several common HIV virus targets and found that carbazole compounds can bind well to reverse transcriptase,so we judged carbazole compounds may exert anti-HIV activity by combining with reverse transcriptase.On this basis,we designed and synthesized 16 carbazole compounds with one-sided double-oxygenated structure and verified that they can stably bind to reverse transcriptase at the molecular docking level.Two of the compounds scored higher than the previous synthesis.This carbazole molecule provides a theoretical basis and reference for our further research on carbazole compounds against HIV virus in the future.