School of Chemistry, Department of Pharmacy, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Mexico City 04510, Mexico.
Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy.
Bioorg Med Chem. 2020 Jun 15;28(12):115539. doi: 10.1016/j.bmc.2020.115539. Epub 2020 May 4.
Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. In this work, we automated the design of a library of lactams by applying a Diversity-Oriented Synthesis strategy called Build/Couple/Pair. We evaluated the novelty and diversity of these compounds by comparing them with lactam moieties contained in approved drugs, natural products, and bioactive compounds from ChEMBL. Finally, depending on their scaffold we classified them into β-, γ-, δ-, ε-, and isolated, fused, bridged and spirolactam groups and we assessed their drug-like and lead-like properties, thus providing the value of this novel in silico designed library for medicinal chemistry applications.
小分子虚拟筛选库已成为鉴定新化合物的有效工具。与实验方法一样，库的质量（定义为结构复杂性和多样性）对于提高筛选活动的成功率至关重要。在这种情况下，定向多样性合成已被证明非常有效，因为所生成的化合物结构复杂，不仅在附属物上不同，而且在分子骨架上也不同。在这项工作中，我们通过应用一种称为 Build/Couple/Pair 的定向多样性合成策略，实现了内酰胺库的自动化设计。我们通过将这些化合物与已批准药物、天然产物和 ChEMBL 中的生物活性化合物中的内酰胺部分进行比较，评估了它们的新颖性和多样性。最后，根据它们的骨架，我们将它们分为 β-、γ-、δ-、ε-和孤立、融合、桥接和螺内酯组，并评估了它们的类药性和类先导化合物性质，从而为药物化学应用提供了这种新型计算机设计库的价值。
