Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Interdisciplinary Center of Marine and Environmental Investigation (CIIMAR/CIMAR), Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal.
Molecules. 2023 May 13;28(10):4073. doi: 10.3390/molecules28104073.
The emergence of multiresistant bacteria and the shortage of antibacterials in the drug pipeline creates the need to search for novel agents. Evolution drives the optimization of the structure of marine natural products to act as antibacterial agents. Polyketides are a vast and structurally diverse family of compounds that have been isolated from different marine microorganisms. Within the different polyketides, benzophenones, diphenyl ethers, anthraquinones, and xanthones have shown promising antibacterial activity. In this work, a dataset of 246 marine polyketides has been identified. In order to characterize the chemical space occupied by these marine polyketides, molecular descriptors and fingerprints were calculated. Molecular descriptors were analyzed according to the scaffold, and principal component analysis was performed to identify the relationships among the different descriptors. Generally, the identified marine polyketides are unsaturated, water-insoluble compounds. Among the different polyketides, diphenyl ethers tend to be more lipophilic and non-polar than the remaining classes. Molecular fingerprints were used to group the polyketides according to their molecular similarity into clusters. A total of 76 clusters were obtained, with a loose threshold for the Butina clustering algorithm, highlighting the large structural diversity of the marine polyketides. The large structural diversity was also evidenced by the visualization trees map assembled using the tree map (TMAP) unsupervised machine-learning method. The available antibacterial activity data were examined in terms of bacterial strains, and the activity data were used to rank the compounds according to their antibacterial potential. This potential ranking was used to identify the most promising compounds (four compounds) which can inspire the development of new structural analogs with better potency and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties.
耐药菌的出现和抗菌药物研发管线的短缺促使人们需要寻找新型药物。海洋天然产物的结构在进化过程中不断优化，以发挥抗菌作用。聚酮类化合物是一类结构多样的化合物，广泛存在于不同的海洋微生物中。在不同的聚酮类化合物中，二苯甲酮、二苯醚、蒽醌和酮类化合物表现出了有前景的抗菌活性。在这项工作中，我们确定了 246 种海洋聚酮类化合物的数据集。为了描述这些海洋聚酮类化合物占据的化学空间，我们计算了分子描述符和指纹。根据支架分析了分子描述符，并进行了主成分分析以确定不同描述符之间的关系。通常，鉴定出的海洋聚酮类化合物是不饱和的、不溶于水的化合物。在不同的聚酮类化合物中，二苯醚类化合物往往比其余类别的化合物更具亲脂性和非极性。分子指纹用于根据分子相似性将聚酮类化合物分为簇。使用 Butina 聚类算法得到了 76 个聚类，聚类算法的阈值较松，突出了海洋聚酮类化合物的结构多样性较大。使用树图（TMAP）无监督机器学习方法组装可视化树图也证明了其结构多样性较大。根据抗菌活性数据的细菌菌株对其进行了检查，并根据抗菌潜力对化合物进行了排序。该潜在排名用于确定最有希望的化合物（四种化合物），这些化合物可以激发新的结构类似物的开发，以提高其效力和吸收、分布、代谢、排泄和毒性（ADMET）性质。
