Abstract：
Cathepsin K is a type of cysteine proteinase that is primarily expressed in osteoclasts and has a key role in the breakdown of bone matrix protein during bone resorption. Many studies suggest that the deficiency of cathepsin K is concomitant with a suppression of osteoclast functioning, therefore rendering the resorptive properties of cathepsin K the most prominent target for osteoporosis. This innovative work has identified a novel anti-osteoporotic agent against Cathepsin K by using a comparison of machine learning and deep learning-based virtual screening followed by their biological evaluation. Out of ten shortlisted compounds, five of the compounds (JFD02945, JFD02944, RJC01981, KM08968 and SB01934) exhibit more than 50% inhibition of the Cathepsin K activity at 0.1 μM concentration and are considered to have a promising inhibitory effect against Cathepsin K. The comprehensive docking, MD simulation, and MM/PBSA investigations affirm the stable and effective interaction of these compounds with Cathepsin K to inhibit its function. Furthermore, the compounds RJC01981, KM08968 and SB01934 are represented to have promising anti-osteoporotic properties for the management of osteoporosis owing to their significantly well predicted ADMET properties.
摘要：
组织蛋白酶K是一种半胱氨酸蛋白酶，主要在破骨细胞中表达，在骨吸收过程中骨基质蛋白的分解中起关键作用。许多研究表明，组织蛋白酶K的缺乏伴随着破骨细胞功能的抑制。因此，使组织蛋白酶K的再吸收特性成为骨质疏松症的最突出目标。这项创新工作通过比较机器学习和基于深度学习的虚拟筛选，然后进行生物学评估，确定了一种针对组织蛋白酶K的新型抗骨质疏松剂。在十个入围化合物中，五个化合物（JFD02945，JFD02944，RJC01981，KM08968和SB01934）在0.1μM浓度下对组织蛋白酶K活性的抑制作用超过50％，被认为对组织蛋白酶K具有有希望的抑制作用。综合对接，MD模拟,MM/PBSA研究证实了这些化合物与组织蛋白酶K的稳定有效的相互作用以抑制其功能。此外，化合物RJC01981、KM08968和SB01934由于其显著良好预测的ADMET性质而被认为具有用于治疗骨质疏松症的有希望的抗骨质疏松性质。
