Inhibiting the oligomerization of mycobacterial DNA-directed RNA polymerase(RNAP)using natural compound via in-silico techniques  

作　　者：Ehssan H.Moglad 

机构地区：[1]Department of Pharmaceutics,College of Pharmacy,Prince Sattam Bin Abdulaziz University,P.O.Box 173 Alkharj 11942,Saudi Arabia [2]Department of Microbiology and Parasitology,Institute of Medicinal and Aromatic Plants Research,The National Center for Research,P.O.Box 2404,Khartoum,Sudan

出　　处：《Medicine in Novel Technology and Devices》2024年第1期97-109,共13页医学中新技术与新装备（英文）

基　　金：We appreciate Prince Sattam bin Abdulaziz University for funding this project(PSAU/2023/R/1444).

摘　　要：Mycobacterium tuberculosis(Mtb)is responsible for the spread of tuberculosis(TB).The current study employed virtual screening of 2569 natural compounds against the DNA-directed RNA polymerase(RNAP)of Mtb to identify the possible binders that can inhibit its function.The in-silico methodology included molecular docking to the compounds,further,the stability and flexibility of the best complexes were studied using molecular dynamics simulation,the MM/GBSA binding free energy technique with energy decomposition,PCA,FEL,steered MD simulation,and umbrella sampling.Individual virtual screenings were conducted for the five RNAP subunits(chains A,B,C,D,and E)to identify a compound capable of inhibiting RNAP oligomerization.A promising compound,isoestradiol 3-benzoate,exhibited a low binding score(−7.28kcal/mol to−8.21kcal/mol)and showed binding ability with all subunits of the protein.Thus,the five complexes with isoestradiol 3-benzoate were selected for molecular dynamics simulation analysis.Furthermore,RMSD showed that isoestradiol 3-benzoate bound with chain E showed the lowest RMSD of 0.49nm,while with chains A and B it had the most stable and consistent conformations with RMSD of 1.75nm and 1.2nm,respectively.The H-bond between isoestradiol 3-benzoate and chains C and E showed the highest occupancy(58.27%,45.33%,and 50.80%,42.25%,11.75%).Moreover,the MMPBSA technique showed that isoestradiol 3-benzoate had a strong association with chains B and C(ΔGbind=−126.25±2.03 and−129.27±2.25).Additionally,free energy decomposition,PCA,FEL-steered MD simulation,and umbrella sampling were also performed to validate the association of the ligand with the protein.Isoestradiol 3-benzoate binds strongly to chains B and E;therefore,it should be considered as viable candidate for inhibiting the formation of RNAP protein complex,concluded in this study.

关 键 词：Mycobacterium tuberculosis DNA-Directed RNA polymerase DOCKING Steered MD simulation Natural compounds Binding free energy Umbrella sampling 

分 类 号：O62[理学—有机化学]