Fragment-to-Lead Medicinal Chemistry Publications in 2018

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.</p

Super congruences and Euler numbers

Let $p>3$ be a prime. We prove that $$\sum_{k=0}^{p-1}\binom{2k}{k}/2^k=(-1)^{(p-1)/2}-p^2E_{p-3} (mod p^3),$$ $$\sum_{k=1}^{(p-1)/2}\binom{2k}{k}/k=(-1)^{(p+1)/2}8/3*pE_{p-3} (mod p^2),$$ $$\sum_{k=0}^{(p-1)/2}\binom{2k}{k}^2/16^k=(-1)^{(p-1)/2}+p^2E_{p-3} (mod p^3)$$, where E_0,E_1,E_2,... are Euler numbers. Our new approach is of combinatorial nature. We also formulate many conjectures concerning super congruences and relate most of them to Euler numbers or Bernoulli numbers. Motivated by our investigation of super congruences, we also raise a conjecture on 7 new series for $\pi^2$, $\pi^{-2}$ and the constant $K:=\sum_{k>0}(k/3)/k^2$ (with (-) the Jacobi symbol), two of which are $$\sum_{k=1}^\infty(10k-3)8^k/(k^3\binom{2k}{k}^2\binom{3k}{k})=\pi^2/2$$ and $$\sum_{k>0}(15k-4)(-27)^{k-1}/(k^3\binom{2k}{k}^2\binom{3k}k)=K.$

Energy landscape of relaxed amorphous silicon

We analyze the structure of the energy landscape of a well-relaxed 1000-atom model of amorphous silicon using the activation-relaxation technique (ART nouveau). Generating more than 40,000 events starting from a single minimum, we find that activated mechanisms are local in nature, that they are distributed uniformly throughout the model and that the activation energy is limited by the cost of breaking one bond, independently of the complexity of the mechanism. The overall shape of the activation-energy-barrier distribution is also insensitive to the exact details of the configuration, indicating that well-relaxed configurations see essentially the same environment. These results underscore the localized nature of relaxation in this material.Comment: 8 pages, 12 figure

A School-Based, Peer Leadership Physical Activity Intervention for 6th Graders: Feasibility and Results of a Pilot Study

Background: The aim of this study was to promote physical activity in 6th graders by developing and testing the feasibility of an enhanced Presidential Active Lifestyle Award (PALA) program comprised of a peer leadership component and innovative exercise resource toolkit including DVDs. Methods: A racially/ethnically diverse sample of students received the standard PALA program (2 control schools, n = 61) or enhanced PALA+Peers program (2 intervention schools, n = 87) during 2006-2007 academic year. Results: Compared with the control condition, the intervention was successful in increasing moderate physical activity in all students (P = .02) and moderate and hard physical activity among girls (P = .03 and P = .04, respectively). Teachers and students reported a high level of satisfaction and receptivity with the intervention. All teachers thought the DVDs were well-received, and 87% of students reported that they would recommend the enhanced program to peers. Conclusion: Coupling peer leadership with DVDs that promote physical activity may be an effective way to increase youth physical activity

Immediate breast reconstruction with a saline implant and AlloDerm, following removal of a Phyllodes tumor

<p>Abstract</p> <p>Background</p> <p>Phyllodes tumors are uncommon tumors of the breast that exhibit aggressive growth. While surgical management of the tumor has been reported, a single surgical approach with immediate breast reconstruction using AlloDerm has not been reported.</p> <p>Case presentation</p> <p>A 22-year-old woman presented with a 4 cm mass in the left breast upon initial examination. Although the initial needle biopsy report indicated a fibroadenoma, the final pathologic report revealed a 6.5 cm × 6.4 cm × 6.4 cm benign phyllodes tumor <it>ex vivo</it>. Treatment was a simple nipple-sparing mastectomy coupled with immediate breast reconstruction. After the mastectomy, a subpectoral pocket was created for a saline implant and AlloDerm was stitched to the pectoralis and serratus muscle in the lower-pole of the breast.</p> <p>Conclusions</p> <p>Saline implant with AlloDerm can be used for immediate breast reconstruction post-mastectomy for treatment of a phyllodes tumor.</p

A model-based analysis of physical and biological controls on ice algal and pelagic primary production in Resolute Passage

A coupled 1-D sea ice-ocean physical-biogeochemical model was developed to investigate the processes governing ice algal and phytoplankton blooms in the seasonally ice-covered Arctic Ocean. The 1-D column is representative of one grid cell in 3-D model applications and provides a tool for parameterization development. The model was applied to Resolute Passage in the Canadian Arctic Archipelago and assessed with observations from a field campaign during spring of 2010. The factors considered to limit the growth of simulated ice algae and phytoplankton were light, nutrients, and in the case of ice algae, ice melt. In addition to the standard simulation, several model experiments were conducted to determine the sensitivity of the simulated ice algal bloom to parameterizations of light, mortality, and pre-bloom biomass. Model results indicated that: (1) ice algae limit subsequent pelagic productivity in the upper 10 m by depleting nutrients to limiting levels; (2) light availability and pre-bloom biomass determine the onset timing of the ice algal bloom; (3) the maximum biomass is relatively insensitive to the pre-bloom biomass, but is limited by nutrient availability; (4) a combination of linear and quadratic parameterizations of mortality rate is required to adequately simulate the evolution of the ice algal bloom; and (5) a sinking rate for large detritus greater than a threshold of ∼10 m d–1 effectively strips the surface waters of the limiting nutrient (silicate) after the ice algal bloom, supporting the development of a deep chlorophyll maximum

Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor

Bortezomib inhibits nuclear factor-κB (NF-κB). Cetuximab is a chimeric mouse–human antibody targeted against epidermal growth factor receptor (EGFR). We hypothesised that concomitant blockade of NF-κB and EGFR signalling would overcome EGFR-mediated resistance to single-agent bortezomib and induce apoptosis through two molecular pathways. The aim of this phase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFR-expressing epithelial tumours. The 21-day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.3–2 mg m−2). Cetuximab was delivered at a dose of 250 mg m−2 on days 1, 8 and 15 (400 mg m−2 day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. No grade ⩾3 haematological toxicity was noted. Non-hematological grade ⩾3 toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mg m−2). Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck. This combination therapy was moderately effective in extensively pretreated patients with non-small cell lung or head and neck cancers and warrants further investigation