Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI 1000 Ljubljana, Slovenia.
Molecules. 2022 Jul 13;27(14):4484. doi: 10.3390/molecules27144484.
Open innovation initiatives provide opportunities for collaboration and sharing of knowledge and experience between industry, academia, and government institutions. Through open innovation, Merck is offering a Mini Library of 80 carefully selected compounds from previous research and development projects to a broader scientific community for testing in academic drug discovery projects. These compounds are predominantly drug-like and cover a broad range of molecular targets. They could potentially interact with other enzymes, receptors, transporters, and ion channels of interest. The Mini Library was tested on seven enzymes (bacterial MurA, MurC ligase, and DdlB enzyme, human MAO-A/B, human BChE, and murine AChE), and several hits were identified. A follow-up series of structural analogues provided by Merck gave a more detailed insight into the accessibility and the quality of the hit compounds. For example, sartan derivatives were moderate inhibitors of MurC, whereas bisarylureas were potent, selective, nanomolar inhibitors of hMAO-B. Importantly, 3--butyl-substituted indoles were identified as low nanomolar selective inhibitors of hBChE. All in all, the hit derivatives provide new starting points for the further exploration of the chemical space of high-quality enzyme inhibitors.
开放式创新举措为工业、学术界和政府机构之间的合作以及知识和经验的共享提供了机会。默克公司通过开放式创新，向更广泛的科学界提供了来自先前研究和开发项目的 80 种精心挑选的化合物的迷你文库，用于学术药物发现项目的测试。这些化合物主要是类药物，涵盖了广泛的分子靶标。它们可能与其他感兴趣的酶、受体、转运体和离子通道相互作用。迷你文库在七种酶（细菌 MurA、MurC 连接酶和 DdlB 酶、人 MAO-A/B、人 BChE 和鼠 AChE）上进行了测试，发现了几个命中。默克公司提供的后续一系列结构类似物更详细地了解了命中化合物的可及性和质量。例如，沙坦衍生物是 MurC 的中度抑制剂，而双芳基脲是 hMAO-B 的有效、选择性、纳摩尔抑制剂。重要的是，3--丁基取代的吲哚被鉴定为 hBChE 的低纳摩尔选择性抑制剂。总而言之，这些命中衍生物为进一步探索高质量酶抑制剂的化学空间提供了新的起点。
