Study On The Structure-activity Relationship And Activity Of The Antitumor Drug Bortezomib Based On Topomer CoMFA

Objective:Due to the complex and diverse structure of proteasome inhibitors,large molecular flexibility,covalent binding,etc.,it has brought great difficulties to quantitative structure-activity relationships,structural optimization,and molecular design research,and there are not many related studies.see.And some inhibitor molecules have shown strong in vitro inhibitory activity,but poor selection specificity,large toxic and side effects,and low bioavailability are still the main problems in the development of such drugs.This project expects to obtain target compounds with high oral bioavailability,long action time,low toxicity,and excellent drug efficacy through computer-aided drug design.Methods:This project took the peptide borate proteasome inhibitor bortezomib as the lead compound,established a Topomer Co MFA model,designed and synthesized the target compound,and measured the activity of the target compound to inhibit the?5 subunit through enzyme experiments.A 3D-QSAR model was established and analyzed,and Gold software was used for covalent docking.Results:The Topomer Co MFA model was established with the template molecule 5r.Its N,r²,and q²were 5,0.694,and 0.931.The isoelectric graph analysis results showed that the R₃position is suitable for negatively charged and relatively sterically hindered groups,and the R₂position is Charged and bulky groups are preferred.The active fragments R₂and R₃were selected by Topomer Search to be 39and 51,and R₂and R₃of 5r were replaced in turn.1989 target compounds were designed,and their predicted activities were all greater than 5r.Seven target compounds were successfully synthesized,and their structures were characterized by ¹H-NMR,¹³C-NMR,and MS.After in vitro enzyme activity test,IC₅₀reached n M level.The docking software was used to analyze the binding mode of the target compound and?5 subunit using the docking software.The target compound bortezomib acts in the same way,and it covalently binds to the oxygen atom of the?5subunit amino acid Thr1 through the C-terminal boric acid moiety.