QSAR Modeling, Molecular Docking and ADMET Study of Aryl Fluorosulfate Derivatives as Potential Anti-TB Agents

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, stands as a global infectious disease presenting substantial public health challenges due to its high incidence and mortality rates. The prolonged use of conventional anti-TB therapies has led to the emergence of severe drug resistance in Mtb, resulting in extended treatment durations, increased costs, poor patient compliance, and reduced cure rates. This phenomenon has posed a significant burden on global TB prevention and control efforts, necessitating a shift in research focus toward the exploration of novel anti-TB drugs. In this context, utilizing QSAR modeling methods, our study systematically investigated the relationship between the chemical structures of 36 aryl fluorosulfate derivatives and their inhibitory activity against Mtb. Robust and predictive Topomer CoMFA and HQSAR models were developed, featuring Topomer CoMFA model parameters: q² = 0.659, r² = 0.969, F = 102.877, N = 6, SEE = 0.138; HQSAR model parameters: q² = 0.705, r² = 0.873, SEE = 0.264, HL = 199, N = 4. Leveraging these models, structural modifications were applied to the compounds using the ZINC15 database, leading to the successful design and screening of three novel compounds with desirable inhibitory activity. Molecular docking and ADMET performance prediction results indicated that these three new compounds exhibit strong binding capabilities and promising pharmaceutical potential. This study provides valuable insights and research directions for the development of aryl fluorosulfate derivatives as potential agents for tuberculosis treatment and as novel drugs.