Bioactive conformational generation of small molecules: A comparative analysis between force-field and multiple empirical criteria based methods

<p>Abstract</p> <p>Background</p> <p>Conformational sampling for small molecules plays an essential role in drug discovery research pipeline. Based on multi-objective evolution algorithm (MOEA), we have developed a conformational generation method called Cyndi in the previous study. In this work, in addition to Tripos force field in the previous version, Cyndi was updated by incorporation of MMFF94 force field to assess the conformational energy more rationally. With two force fields against a larger dataset of 742 bioactive conformations of small ligands extracted from PDB, a comparative analysis was performed between pure force field based method (FFBM) and multiple empirical criteria based method (MECBM) hybrided with different force fields.</p> <p>Results</p> <p>Our analysis reveals that incorporating multiple empirical rules can significantly improve the accuracy of conformational generation. MECBM, which takes both empirical and force field criteria as the objective functions, can reproduce about 54% (within 1Å RMSD) of the bioactive conformations in the 742-molecule testset, much higher than that of pure force field method (FFBM, about 37%). On the other hand, MECBM achieved a more complete and efficient sampling of the conformational space because the average size of unique conformations ensemble per molecule is about 6 times larger than that of FFBM, while the time scale for conformational generation is nearly the same as FFBM. Furthermore, as a complementary comparison study between the methods with and without empirical biases, we also tested the performance of the three conformational generation methods in MacroModel in combination with different force fields. Compared with the methods in MacroModel, MECBM is more competitive in retrieving the bioactive conformations in light of accuracy but has much lower computational cost.</p> <p>Conclusions</p> <p>By incorporating different energy terms with several empirical criteria, the MECBM method can produce more reasonable conformational ensemble with high accuracy but approximately the same computational cost in comparison with FFBM method. Our analysis also reveals that the performance of conformational generation is irrelevant to the types of force field adopted in characterization of conformational accessibility. Moreover, post energy minimization is not necessary and may even undermine the diversity of conformational ensemble. All the results guide us to explore more empirical criteria like geometric restraints during the conformational process, which may improve the performance of conformational generation in combination with energetic accessibility, regardless of force field types adopted.</p

Electric power network fractal and its relationship with power system fault

Mreža elektro-energetskog sustava ima karakteristike fraktala. Ima osnovnu značajku složene mreže: sličnost samoj sebi. Autori su najprije izračunali vrijednosti fraktalne dimenzije za nekoliko elektro-energetskih rešetki, uključujući sustav 9 sabirnica WSCC (Western Systems Coordinating Council), sustav 14 sabirnica IEEE, sustav 30 sabirnica IEEE, sustav 39 sabirnica IEEE, sustav 118 sabirnica IEEE i sustav 300 sabirnica IEEE, kao i nekoliko stvarnih energetskih rešetki kao što su 500 kV glavne China Southern Power Grid (CSPG), 500 kV glavne energetske rešetke provincije Guangdong te 500 kV i 220 kV miješane energetske rešetke provincije Guangdong, itd. Na temelju fraktalne vrijednosti energetske rešetke analizirana je usporedba i odnos između fraktalne vrijednosti i intenziteta kvarenja energetskog sustava. Osnovni je zaključak da će za isti nivo napona, što je veća skala, energetska rešetka vjerojatno imati veću fraktalnu vrijednost i veći intenzitet kvarenja. Kod iste skale, što je gušća energetska rešetka to će vjerojatno biti veća fraktalna vrijednost i veći intenzitet kvarenja rešetke. Zaključci pružaju novi uvid u prosudbu statusa osjetljivosti energetskog sustava s interdisciplinarnog gledišta te voditi do novih smjerova u istraživanju.Electric power system network is with fractal characteristic. It has the basic feature of a complex network: self-similarity. The authors first calculated the fractal dimension values for several electric power grids, including WSCC (Western Systems Coordinating Council) 9 bus system, IEEE14 bus system, IEEE 30 bus system, IEEE 39 bus system, IEEE 118 bus system and IEEE 300 bus system; as well as some real power grids such as China Southern Power Grid (CSPG) 500 kV main power grid, Guangdong province 500 kV main power grid, and Guangdong province 500 kV and 220 kV mixed power grid, etc. Based on the power grid fractal value, a comparison and relationship between the fractal value and power system failure rate is analysed. The basic conclusion is that for the same voltage level, the larger the scale is, the larger fractal value and higher failure rate the power grid will possibly have. For the same scale, the denser the power grid, the larger fractal value and higher failure rate the power grid will probably have. The conclusions provide a new vision on the power system vulnerability status judgment from an interdisciplinary view and lead to a new research direction

Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

Drug-target residence time (t = 1/koff, where koff is the dissociation rate constant) has become an important index in discovering betteror best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, koff and activation free energy of dissociation (ΔG≠ off). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated.We applied this method to simulate the binding event of the anti-Alzheimer’s disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/ mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect thismethodology to be widely applicable to drug discovery and development

Analysis of the geographic distribution of HFRS in Liaoning Province between 2000 and 2005

<p>Abstract</p> <p>Background</p> <p>Hemorrhagic fever with renal syndrome (HFRS) is endemic in Liaoning Province, China, and this province was the most serious area affected by HFRS during 2004 to 2005. In this study, we conducted a spatial analysis of HFRS cases with the objective to determine the distribution of HFRS cases and to identify key areas for future public health planning and resource allocation in Liaoning Province.</p> <p>Methods</p> <p>The annual average incidence at the county level was calculated using HFRS cases reported between 2000 and 2005 in Liaoning Province. GIS-based spatial analyses were conducted to detect spatial distribution and clustering of HFRS incidence at the county level, and the difference of relative humidity and forestation between the cluster areas and non-cluster areas was analyzed.</p> <p>Results</p> <p>Spatial distribution of HFRS cases in Liaoning Province from 2000 to 2005 was mapped at the county level to show crude incidence, excess hazard, and spatial smoothed incidence. Spatial cluster analysis suggested 16 and 41 counties were at increased risk for HFRS (p < 0.01) with the maximum spatial cluster sizes at ≤ 50% and ≤ 30% of the total population, respectively, and the analysis showed relative humidity and forestation in the cluster areas were significantly higher than in other areas.</p> <p>Conclusion</p> <p>Some clustering of HFRS cases in Liaoning Province may be etiologically linked. There was strong evidence some HFRS cases in Liaoning Province formed clusters, but the mechanism underlying it remains unknown. In this study we found the clustering was consistent with the relative humidity and amount of forestation, and showed data indicating there may be some significant relationships.</p

Inherent Dynamics of the Acid-Sensing Ion Channel 1 Correlates with the Gating Mechanism

A combination of computational and experimental approaches reveals the dynamics of ASIC1 gating, involving a deformation of the channel that triggers “twist-to-open” motions of the channel pore

Seizing the window of opportunity to mitigate the impact of climate change on the health of Chinese residents

The health threats posed by climate change in China are increasing rapidly. Each province faces different health risks. Without a timely and adequate response, climate change will impact lives and livelihoods at an accelerated rate and even prevent the achievement of the Healthy and Beautiful China initiatives. The 2021 China Report of the Lancet Countdown on Health and Climate Change is the first annual update of China’s Report of the Lancet Countdown. It comprehensively assesses the impact of climate change on the health of Chinese households and the measures China has taken. Invited by the Lancet committee, Tsinghua University led the writing of the report and cooperated with 25 relevant institutions in and outside of China. The report includes 25 indicators within five major areas (climate change impacts, exposures, and vulnerability; adaptation, planning, and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement) and a policy brief. This 2021 China policy brief contains the most urgent and relevant indicators focusing on provincial data: The increasing health risks of climate change in China; mixed progress in responding to climate change. In 2020, the heatwave exposures per person in China increased by 4.51 d compared with the 1986–2005 average, resulting in an estimated 92% increase in heatwave-related deaths. The resulting economic cost of the estimated 14500 heatwave-related deaths in 2020 is US$176 million. Increased temperatures also caused a potential 31.5 billion h in lost work time in 2020, which is equivalent to 1.3% of the work hours of the total national workforce, with resulting economic losses estimated at 1.4% of China’s annual gross domestic product. For adaptation efforts, there has been steady progress in local adaptation planning and assessment in 2020, urban green space growth in 2020, and health emergency management in 2019. 12 of 30 provinces reported that they have completed, or were developing, provincial health adaptation plans. Urban green space, which is an important heat adaptation measure, has increased in 18 of 31 provinces in the past decade, and the capacity of China’s health emergency management increased in almost all provinces from 2018 to 2019. As a result of China’s persistent efforts to clean its energy structure and control air pollution, the premature deaths due to exposure to ambient particulate matter of 2.5 μm or less (PM2.5) and the resulting costs continue to decline. However, 98% of China’s cities still have annual average PM2.5 concentrations that are more than the WHO guideline standard of 10 μg/m3. It provides policymakers and the public with up-to-date information on China’s response to climate change and improvements in health outcomes and makes the following policy recommendations. (1) Promote systematic thinking in the related departments and strengthen multi-departmental cooperation. Sectors related to climate and development in China should incorporate health perspectives into their policymaking and actions, demonstrating WHO’s and President Xi Jinping’s so-called health-in-all-policies principle. (2) Include clear goals and timelines for climate-related health impact assessments and health adaptation plans at both the national and the regional levels in the National Climate Change Adaptation Strategy for 2035. (3) Strengthen China’s climate mitigation actions and ensure that health is included in China’s pathway to carbon neutrality. By promoting investments in zero-carbon technologies and reducing fossil fuel subsidies, the current rebounding trend in carbon emissions will be reversed and lead to a healthy, low-carbon future. (4) Increase awareness of the linkages between climate change and health at all levels. Health professionals, the academic community, and traditional and new media should raise the awareness of the public and policymakers on the important linkages between climate change and health.</p