Herein, the LASSBio Chemical Library is presented as a valuable source of compounds for screening to identify hits suitable for subsequent hit-to-lead optimization stages. A feature of the LASSBio Chemical Library worth highlighting is the fact that it is a smart library designed by medicinal chemists with pharmacological activity as the main priority. The great majority of the compounds part of this library have shown in vivo activity in animal models, which is an indication that they possess overall favorable bioavailability properties and, hence, adequate pharmacokinetic profiles. This, in turn, is supported by the fact that approximately 85% of the compounds are compliant with Lipinski’s rule of five and ca. 95% are compliant with Veber’s rules, two important guidelines for oral bioavailability. In this work it is presented a virtual screening methodology combining a pharmacophore-based model and an empirical Gibbs free energy-based model for the ligand–protein interaction to explore the LASSBio Chemical Library as a source of new hits for the inhibition of the phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) enzyme, which is related to the development of viral infections (including enteroviruses, SARS coronavirus, and hepatitis C virus), cancers and neurological diseases. The approach resulted in the identification of two hits, LASSBio-1799 (7) and LASSBio-1814 (10), which inhibited the target enzyme with IC₅₀ values of 3.66 μM and IC₅₀ and 6.09 μM, respectively. This study also enabled the determination of the structural requirements for interactions with the active site of PI4KIIIβ, demonstrating the importance of both acceptor and donor hydrogen bonding groups for forming interactions with binding site residues Val598 and Lys549.

在这里，LASSBio 化学库作为一种有价值的化合物来源，用于筛选以识别适合后续命中到先导优化阶段的命中。LASSBio 化学库的一个值得强调的特点是，它是由药物化学家设计的以药理活性为主要优先事项的智能库。该文库中的绝大多数化合物部分在动物模型中显示出体内活性，这表明它们具有总体良好的生物利用度特性，因此具有足够的药代动力学特征。反过来，大约 85% 的化合物符合 Lipinski 的五项规则和ca. 95% 符合 Veber 的规则，这是口服生物利用度的两个重要指南。在这项工作中，它提出了一种虚拟筛选方法，结合了基于药效团的模型和基于经验的吉布斯自由能模型，用于配体-蛋白质相互作用，以探索 LASSBio 化学库作为抑制磷脂酰肌醇 4 的新结果的来源-激酶IIIβ（PI4KIIIβ）酶，与病毒感染（包括肠道病毒、SARS冠状病毒和丙型肝炎病毒）、癌症和神经系统疾病的发展有关。该方法鉴定出两个命中物 LASSBio-1799 ( 7 ) 和 LASSBio-1814 ( 10 )，它们抑制目标酶的 IC ₅₀值为 3.66 μM 和 IC ₅₀和 6.09 μM，分别。该研究还能够确定与 PI4KIIIβ 活性位点相互作用的结构要求，证明受体和供体氢键基团对于与结合位点残基 Val598 和 Lys549 形成相互作用的重要性。