Identification and characterization of the druggable kinase targets of olmesartan and its analogues from a systematic kinase –chemical interaction profile in atherosclerosis

Publication date: March 2018 Source:Journal of Molecular Graphics and Modelling, Volume 80 Author(s): Rui-Juan Zhuang, Wei-Dong Jin, Xiao-Yan Wang, Xue-Ming Wu Olmesartan (OL) is the pharmacologically active metabolite of Olmesartan medoxomil (OM), an FDA-approved angiotensin II receptor antagonist for administrating cardiovascular diseases. The drug has been found to have potential effects on diverse protein kinase signaling involved in the pathogenesis of atherosclerosis, either by directly inhibiting the hub kinases or by indirectly modulating marginal members in the signaling pathways. In the present study, we computationally model the kinase–chemical Interaction Profile between six OL-related chemicals (i.e. OL, OM, Valsartan [VL], Losartan [LS], Candesartan [CD] and Telmisartan [TL]) and 23 human protein kinases in atherosclerosis. The profile is analyzed systematically at molecular level to identify unexpected kinase targets for OL. There is a good consistence between co-citation frequency and affinity scoring for the chemical association with kinase candidates; the OL and its analogs VL and LS exhibit a similar binding profile to the atherosclerosis kinase spectrum. It is suggested that the Ser/Thr-specific kinases PI3Kα and ROCK1 are potential druggable targets of OL for atherosclerosis therapy. As a paradigm, kinase assays reveal that the inhibitory potency of OL and Y-27632 (positive control) on ROCK1 is determined at micromolar level, while the OM (negati...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research