Loo Jason S E, Emtage Abigail L, Murali Lahari, Lee Sze Siew, Kueh Alvina L W, Alexander Stephen P H
School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University No. 1 Jalan Taylors 47500 Subang Jaya Selangor Malaysia
School of Pharmacy, The University of Nottingham Malaysia Campus Jalan Broga 43500 Semenyih Selangor Malaysia.
RSC Adv. 2019 May 21;9(28):15949-15956. doi: 10.1039/c9ra01095e. eCollection 2019 May 20.
The therapeutic potential of the CB1 cannabinoid receptor remains underexploited with only a few synthetic ligands on the market. The crystal structures of both the inactive and active-state CB1 receptor have recently been solved, allowing for unprecedented opportunities in structure-based drug discovery applications such as virtual screening. In this study, we have investigated the virtual screening performance of the active and inactive-state CB1 crystal structures and their ability to discriminate between agonist and inverse agonist/antagonist ligands. The ligands of inactive and active-state CB1 receptor crystal structures were then swapped cross-docking and the resulting structures were subjected to microsecond molecular dynamics (MD) simulations, followed by virtual screening of the MD-extracted structures. The original crystal structures were found to be biased towards ligands matching their activation state during virtual screening. MD simulations of the cross-docked CB1 structures resulted in a minor shift of receptor conformation towards the inactive state for the active-state CB1 structure complexed with the inverse agonist taranabant. Effects on virtual screening were more pronounced, as MD simulations of the cross-docked receptor-ligand complexes reversed the ligand bias in virtual screening observed with the original crystal structures. The simulations also produced receptor conformations that outperformed the crystal structures in virtual screening and in predicting the binding pose of the cognate ligand. The findings of this study highlight the potential of cross-docking and MD simulations to reverse the ligand bias of crystal structures, which may be useful when the crystal structure of only one activation state is available.
CB1大麻素受体的治疗潜力尚未得到充分开发，市场上只有少数几种合成配体。最近已解析出非活性和活性状态CB1受体的晶体结构，这为基于结构的药物发现应用（如虚拟筛选）带来了前所未有的机遇。在本研究中，我们研究了活性和非活性状态CB1晶体结构的虚拟筛选性能及其区分激动剂和反向激动剂/拮抗剂配体的能力。然后交换非活性和活性状态CB1受体晶体结构的配体进行交叉对接，并对所得结构进行微秒级分子动力学（MD）模拟，随后对MD提取的结构进行虚拟筛选。研究发现，在虚拟筛选过程中，原始晶体结构偏向于与它们的激活状态相匹配的配体。对于与反向激动剂塔那班结合的活性状态CB1结构，交叉对接的CB1结构的MD模拟导致受体构象向非活性状态发生轻微偏移。对虚拟筛选的影响更为显著，因为交叉对接的受体-配体复合物的MD模拟逆转了原始晶体结构在虚拟筛选中观察到的配体偏向。这些模拟还产生了在虚拟筛选和预测同源配体结合姿势方面优于晶体结构的受体构象。本研究结果突出了交叉对接和MD模拟在逆转晶体结构配体偏向方面的潜力，当只有一种激活状态的晶体结构可用时，这可能会很有用。
