急性髓系白血病是一种严重的疾病，影响干细胞，并导致无法控制的髓母细胞增殖和积累。广泛的研究致力于寻找快速、有效的化疗药物。一种潜在的选择是BRD4抑制剂，已知具有抑制细胞增殖的作用。研究表明磺胺衍生物是有效的BRD4抑制剂的重要结构元素。为了实现这个目标，我们采用了三维定量构效关系（3D-QSAR）分子建模技术，包括CoMFA、CoMSIA和HQSAR模型，以及分子对接和分子动力学模拟。对2D/3D QSAR模型进行内部和外部的验证，证明了它们的稳健性和可靠性。来自CoMFA、CoMSIA和HQSAR分析的等值图在设计有效的BRD4抑制剂方面起到了关键作用。重要的是，我们的研究结果突出了在吡啶酮环上引入较大取代基和在甲氧基取代苯环上引入疏水/静电取代基的优势，这有助于与BRD4靶点的相互作用。通过分子对接模拟，研究了新化合物与BRD4受体（PDB ID:4BJX）的相互作用模式，发现了有利的结合能，并通过形成与关键蛋白残基的氢键和疏水键来支持。此外，基于ADMET分析，这些新型抑制剂表现出良好的口服生物利用度和无毒性。此外，从58系列中选择最活跃的一种与新设计的化合物一起进行分子动力学模拟，以分析它们的行为。模拟结果提供了额外的证据，支持分子对接结果，并确认所分析分子在轨迹上的持续稳定性。该结果可作为设计和开发新型有效的BRD4抑制剂的有价值参考。Ramaswamy H. Sarma郑重声明。

Acute myeloid leukemia, a serious condition affecting stem cells, drives uncontrollable myeloblast proliferation, leading to accumulation. Extensive research seeks rapid, effective chemotherapeutics. A potential option is a BRD4 inhibitor, known for suppressing cell proliferation. Sulfonamide derivatives probed essential structural elements for potent BRD4 inhibitors. To achieve this goal, we employed 3D-QSAR molecular modeling techniques, including CoMFA, CoMSIA, and HQSAR models, along with molecular docking and molecular dynamics simulations. The validation of the 2D/3D QSAR models, both internally and externally, underscores their robustness and reliability. The contour plots derived from CoMFA, CoMSIA, and HQSAR analyses played a pivotal role in shaping the design of effective BRD4 inhibitors. Importantly, our findings highlight the advantageous impact of incorporating bulkier substituents on the pyridinone ring and hydrophobic/electrostatic substituents on the methoxy-substituted phenyl ring, enhancing interactions with the BRD4 target. The interaction mode of the new compounds with the BRD4 receptor (PDB ID: 4BJX) was investigated using molecular docking simulations, revealing favorable binding energies, supported by the formation of hydrogen and hydrophobic bonds with key protein residues. Moreover, these novel inhibitors exhibited good oral bioavailability and demonstrated non-toxic properties based on ADMET analysis. Furthermore, the newly designed compounds along with the most active one from series 58, underwent a molecular dynamics simulation to analyze their behavior. The simulation provided additional evidence to support the molecular docking results, confirming the sustained stability of the analyzed molecules over the trajectory. This outcome could serve as a valuable reference for designing and developing novel and effective BRD4 inhibitors.Communicated by Ramaswamy H. Sarma.