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These represented single and multiple amino acid substitutions and were characterized with a spectrum of metrics including binding, cellular activity, activity in a p53 independent counter-screen, circular dichroism spectroscopy, experimental LogD, calculated ALogP, solubility, NanoClick permeability 22 , and membrane disruption (as measured by lactate dehydrogenase (LDH) cytoplasmic release), (Supplementary Data 1)

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Phase 2 Side-Effect Frequencies at 4.5 mg/week (Lancet 2021) Side Effect Nausea Incidence at 4.5 mg/week 47% Side Effect Injection-site reactions Incidence at 4.5 mg/week 43% Side Effect Constipation Incidence at 4.5 mg/week 21% Side Effect Fatigue Incidence at 4.5 mg/week 20% Side Effect Allergic reactions (any) Incidence at 4.5 mg/week 10% Side Effect Vomiting Incidence at 4.5 mg/week 8% Side Effect Loose stools Incidence at 4.5 mg/week 7% Side Effect Headache Incidence at 4.5 mg/week 7% Side Effect Indigestion Incidence at 4.5 mg/week 4% Incidence was lower at lower doses

Nutritional Considerations: Because orlistat decreases fat absorption, it can also reduce the absorption of fat-soluble vitamins (A, D, E, and K)