The hit-to-lead optimization of 1,2,3,4,4a,9a-hexahydro-1H-xanthenes as glucocorticoid receptor antagonists

The structure–activity relationship（SAR） study of a 1 2 3 4 4a 9a-hexahydro-1H-xanthene series of selective,human glucocorticoid receptor a（hGRa） antagonists is reported.Compounds were screened using hydroxyapatite-based GR binding and MMTV-Luc co-transfection reporter gene assays.Four different regions of the scaffold were modified to assess the effects on hGRa antagonism and related potency.Compound 8d exhibits an 8-fold better bioactivity than the original hit 1a,as well as an improved chemical stability,which make it a promising lead for the subsequent optimization.

Winter Wheat Yield Estimation Based on Sparrow Search Algorithm Combined with Random Forest:A Case Study in Henan Province,China

Precise and timely prediction of crop yields is crucial for food security and the development of agricultural policies.However,crop yield is influenced by multiple factors within complex growth environments.Previous research has paid relatively little attention to the interference of environmental factors and drought on the growth of winter wheat.Therefore,there is an urgent need for more effective methods to explore the inherent relationship between these factors and crop yield,making precise yield prediction increasingly important.This study was based on four type of indicators including meteorological,crop growth status,environmental,and drought index,from October 2003 to June 2019 in Henan Province as the basic data for predicting winter wheat yield.Using the sparrow search al-gorithm combined with random forest(SSA-RF)under different input indicators,accuracy of winter wheat yield estimation was calcu-lated.The estimation accuracy of SSA-RF was compared with partial least squares regression(PLSR),extreme gradient boosting(XG-Boost),and random forest(RF)models.Finally,the determined optimal yield estimation method was used to predict winter wheat yield in three typical years.Following are the findings:1)the SSA-RF demonstrates superior performance in estimating winter wheat yield compared to other algorithms.The best yield estimation method is achieved by four types indicators’composition with SSA-RF)(R^(2)=0.805,RRMSE=9.9%.2)Crops growth status and environmental indicators play significant roles in wheat yield estimation,accounting for 46%and 22%of the yield importance among all indicators,respectively.3)Selecting indicators from October to April of the follow-ing year yielded the highest accuracy in winter wheat yield estimation,with an R^(2)of 0.826 and an RMSE of 9.0%.Yield estimates can be completed two months before the winter wheat harvest in June.4)The predicted performance will be slightly affected by severe drought.Compared with severe drought year(2011)(R^(2)=0.680)and normal year(2017)(R^(2)=0.790),the SSA-RF model has higher prediction accuracy for wet year(2018)(R^(2)=0.820).This study could provide an innovative approach for remote sensing estimation of winter wheat yield.yield.

Topology optimization of compliant adaptive wing leading edge with composite materials

An approach for designing the compliant adaptive wing leading edge with composite material is proposed based on the topology optimization. Firstly, an equivalent constitutive relationship of laminated glass fiber reinforced epoxy composite plates has been built based on the symmetric laminated plate theory. Then, an optimization objective function of compliant adaptive wing leading edge was used to minimize the least square error（LSE） between deformed curve and desired aerodynamics shape. After that, the topology structures of wing leading edge of different glass fiber ply-orientations were obtained by using the solid isotropic material with penalization（SIMP） model and sensitivity filtering technique. The desired aerodynamics shape of compliant adaptive wing leading edge was obtained based on the proposed approach. The topology structures of wing leading edge depend on the glass fiber ply-orientation. Finally, the corresponding morphing experiment of compliant wing leading edge with composite materials was implemented, which verified the morphing capability of topology structure and illustrated the feasibility for designing compliant wing leading edge. The present paper lays the basis of ply-orientation optimization for compliant adaptive wing leading edge in unmanned aerial vehicle（UAV） field.

PLANNED LEAD TIME OPTIMIZATION IN MATERIAL REQUIREMENT PLANNING ENVIRONMENT FOR MULTILEVEL PRODUCTION SYSTEMS

This paper deals with the problem of planned lead time calculation in a Material Requirement Planning （MRP） environment under stochastic lead times. The objective is to minimize the sum of holding and backlogging costs. The proposed approach is based on discrete time inventory control where the decision variables are integer. Two types of systems are considered： multi-level serial-production and assembly systems. For the serial production systems （one type of component at each level）, a mathematical model is suggested. Then, it is proven that this model is equivalent to the well known discrete Newsboy Model. This directly provides the optimal values for the planned lead times. For multilevel assembly systems, a dedicated model is proposed and some properties of the decision variables and objective function are proven. These properties are used to calculate lower and upper limits on the decision variables and lower and upper bounds on the objective function. The obtained limits and bounds open the possibility to develop an efficient optimization algorithm using, for example, a Branch and Bound approach. The paper presents the proposed models in detail with corresponding proofs and se＇~eral numerical examples. Some advantages of the suggested models and perspectives of this research are discussed.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.