Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

The forced move to online learning in the arrival and persistence of the COVID-19 pandemic underscored the present lack of models for fully online general chemistry laboratory courses. While there exist a fair number of simulation platforms, video libraries, and one-off virtual experiments, a lack of complete general chemistry lab online courses necessitated the development of such an experience. By leveraging freely available simulations and videos, we were able to design two synchronous online delivery lab courses in the summer of 2020. Herein, the courses are described with accompanying analysis probing student perceptions of their experiences.

Background-Myocardial stunning may cause prolonged left ventricular dysfunction after exercise-induced ischemia that can be attenuated by calcium antagonists in animal models. To assess their effects in humans, we performed a randomized, double-blind crossover study comparing the calcium antagonist amlodipine (10 mg once daily) versus isosorbide mononitrate (ISMN, 50 mg once daily) on postexercise stunning. Methods and Results-Twenty-four men with chronic stable angina and normal left ventricular function underwent serial quantitative exercise stress echocardiography after 3 weeks on each treatment to assess the degree of postexercise stunning with simultaneous sestamibi single-photon emission computed tomography perfusion scans at peak stress to quantify the ischemic burden. Exercise time (Pϭ1), maximum ST depression (Pϭ0.48), and sestamibi single-photon emission computed tomography scores (Pϭ0.17) were unchanged between treatments. Stunning occurred more often with ISMN than amlodipine (82% versus 48%). The global and segmental stress echocardiography parameters of stunning were attenuated in patients while taking amlodipine compared with ISMN. Shortening fractions and ejection fractions were less impaired 30 minutes after exercise in patients receiving amlodipine (3.5Ϯ1.4% versus 2.5Ϯ1.4%, Pϭ0.014, and 59.7Ϯ5.4% versus 54.5Ϯ8%, PϽ0.001); similarly, the isovolumic relaxation period was less prolonged with amlodipine (93Ϯ15.5 versus 106.3Ϯ14.9 ms, Pϭ0.018). Conclusions-Despite comparable levels of ischemia, amlodipine attenuated stunning when compared with ISMN. This beneficial effect may relate to a prevention of the calcium overload implicated in the pathogenesis of stunning.(Circulation. 1998;98:749-756.)

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