Kharatyan Levon, Gevorgyan Smbat, Khachatryan Hamlet, Shavina Anastasiya, Hakobyan Astghik, Matevosyan Mher, Zakaryan Hovakim
Denovo Sciences Inc, Yerevan, 0060, Armenia.
Laboratory of Antiviral Drug Discovery, Institute of Molecular Biology of NAS, Yerevan, 0014, Armenia.
BMC Chem. 2025 Jun 5;19(1):159. doi: 10.1186/s13065-025-01540-z.
This study presents cheminformatics analysis of the antiviral chemical space targeting human influenza A and B viruses. By curating 407,366 small molecules from ChEMBL and PubChem, we evaluated physicochemical properties, structural motifs, and activity trends across phenotypic and target-based assays. We found that 90.6% of evaluated molecules met Lipinski's Rule of Five, with active compounds exhibiting higher topological polar surface area and hydrogen bond donor groups. Target-specific analyses revealed distinct profiles for neuraminidase (NA) and hemagglutinin (HA) inhibitors, including larger molecular weights and increased rotatable bonds. Structural characterization identified cyclohexene, dihydropyran, and pyrimidine rings as prevalent in highly active molecules, while phthalimide motifs correlated with inactivity. Clustering of phenotypic assay data highlighted four promising and unique antiviral candidates, with unexplored chemical space. We also identified five multi-target scaffolds, including the curcumin-like scaffold, demonstrating dual inhibitory potential against two viral proteins. Molecular docking experiments on molecules within one of these multi-target scaffolds indicated their potential as initial hit candidates. Combined RMSD, PDF and DCCM analyses across molecular dynamics simulations elucidated the binding behaviour of five curcumin-like candidates. Two ligands remained as stable as the reference antivirals, one showed target-specific loss of affinity, and two dissociated rapidly, indicating that the stable pair should be prioritised for subsequent in vitro validation. Overall, the findings of this study can aid computer-aided drug design efforts, contributing to the development of novel antiviral agents against human influenza viruses.
本研究展示了针对甲型和乙型人类流感病毒的抗病毒化学空间的化学信息学分析。通过整理来自ChEMBL和PubChem的407,366个小分子，我们评估了理化性质、结构基序以及跨表型和基于靶点测定的活性趋势。我们发现，90.6%的评估分子符合Lipinski的五规则，活性化合物表现出更高的拓扑极性表面积和氢键供体基团。靶点特异性分析揭示了神经氨酸酶（NA）和血凝素（HA）抑制剂的不同特征，包括更大的分子量和增加的可旋转键。结构表征确定环己烯、二氢吡喃和嘧啶环在高活性分子中普遍存在，而邻苯二甲酰亚胺基序与无活性相关。表型测定数据的聚类突出了四个有前景且独特的抗病毒候选物，其具有未被探索的化学空间。我们还鉴定了五个多靶点支架，包括姜黄素样支架，证明了其对两种病毒蛋白的双重抑制潜力。对这些多靶点支架之一内的分子进行分子对接实验表明它们作为初始命中候选物的潜力。跨分子动力学模拟的组合RMSD、PDF和DCCM分析阐明了五个姜黄素样候选物的结合行为。两个配体与参考抗病毒药物一样稳定，一个显示出靶点特异性的亲和力丧失，两个迅速解离，表明稳定的一对应优先用于后续的体外验证。总体而言，本研究的结果有助于计算机辅助药物设计工作，为开发新型抗人类流感病毒药物做出贡献。
