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The win followed the victory for Wawrinka's girlfriend Donna Vekic, who demolished fourth seed Sloane Stephens, earlier in the day.
World No. 2 Rafael Nadal remained on course for his third ATP Mexico Open title.
But the three-time Grand Slam champion is a 'little bit underestimated,' feels his long-time coach.
Swiss Wawrinka, who won the first of his three Grand Slams at Melbourne Park in 2014, broke Zverev twice early in the opening set to breeze through the opening set but the 22-year-old German came roaring back into the contest.
Reilly Opelka came through 7-5, 3-6, 4-6, 6-4, 8-6 against the 22nd seeded Swiss for the biggest win of his career.
After dropping the second set, Djokovic immediately called for medical attention and sat courtside without his shirt on while the trainer massaged his shoulder.
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