It is well known that bromodomain-containing protein 4 (BRD4) has been thought as a promising target utilized for treating various human diseases, such as inflammatory disorders, malignant tumours, acute myelogenous leukaemia (AML), bone diseases, etc. For this study, molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA) were integrated together to uncover binding modes of inhibitors 8P9, 8PU, and 8PX to BRD4(1). The results obtained from binding free energy calculations show that van der Waals interactions act as the main regulator in bindings of inhibitors to BRD4(1). The information stemming from PCA reveals that inhibitor associations extremely affect conformational changes, internal dynamics, and movement patterns of BRD4(1). Residue-based free energy decomposition method was wielded to unveil contributions of independent residues to inhibitor bindings and the data signify that hydrogen bonding interactions and hydrophobic interactions are decisive factors affecting bindings of inhibitors to BRD4(1). Meanwhile, eight residues Trp81, Pro82, Val87, Leu92, Leu94, Cys136, Asn140, and Ile146 are recognized as the common hot interaction spots of three inhibitors with BRD4(1). The results from this work are expected to provide a meaningfully theoretical guidance for design and development of effective inhibitors inhibiting of the activity of BRD4.

众所周知，含溴结构域蛋白4（BRD4）被认为是用于治疗各种人类疾病（如炎症性疾病，恶性肿瘤，急性髓性白血病（AML），骨骼疾病等）的有希望的靶标。对于本研究，分子动力学（MD）模拟，结合自由能计算和主成分分析（PCA）集成在一起，以揭示抑制剂8P9、8PU和8PX与BRD4（1）的结合模式。从结合自由能计算中获得的结果表明，范德华相互作用是抑制剂与BRD4（1）结合的主要调节剂。来自PCA的信息表明，抑制剂的结合极大地影响BRD4（1）的构象变化，内部动力学和运动模式。运用基于残基的自由能分解法揭示了独立​​残基对抑制剂结合的贡献，数据表明氢键相互作用和疏水相互作用是影响抑制剂与BRD4（1）结合的决定性因素。同时，八个残基Trp81，Pro82，Val87，Leu92，Leu94，Cys136，Asn140和Ile146被认为是三种抑制剂与BRD4（1）共同的热相互作用点。这项工作的结果有望为设计和开发有效抑制BRD4活性的抑制剂提供有意义的理论指导。八个残基Trp81，Pro82，Val87，Leu92，Leu94，Cys136，Asn140和Ile146被认为是三种抑制剂与BRD4（1）共同的热点相互作用点。这项工作的结果有望为设计和开发有效抑制BRD4活性的抑制剂提供有意义的理论指导。八个残基Trp81，Pro82，Val87，Leu92，Leu94，Cys136，Asn140和Ile146被认为是三种抑制剂与BRD4（1）共同的热点相互作用点。这项工作的结果有望为设计和开发有效抑制BRD4活性的抑制剂提供有意义的理论指导。