Design and synthesis of hybrids of diarylpyrimidines and diketo acids as HIV-1 inhibitors

Xue, Ping; Lu, Huan-Huan; Zhu, Yuan‐Yuan; Ju, Xin; Pannecouque, Christophe; Zheng, Xuezhe; Liu, Gen-Yan; Zhang, Xiulan; Gu, Shuang‐Xi

doi:10.1016/j.bmcl.2017.03.009

Cited by 13 publications

(1 citation statement)

References 19 publications

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“…Additionally, π–π stacking interactions were found between the left phenyl ring of compound 43 and aromatic amino acid residues such as Tyr188, Tyr181, and Trp229 [ 11 , 19 ]. As shown in Figure 7 a, the left phenyl group is parallel to Tyr181 or Tyr188, and the 4-CH 3 on the phenyl ring points towards the highly conserved Trp229.…”

Section: Resultsmentioning

confidence: 99%

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Liu

Wang

Wan

et al. 2018

IJMS

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Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure–activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q2 = 0.679, R2 = 0.983, and rpred2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q2 = 0.734, R2 = 0.985, and rpred2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C4-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π–π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.

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Section: Resultsmentioning

confidence: 99%