In silico strategies on prion pathogenic conversion and inhibition from PrPC –PrPSc

Introduction: To date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrP^C, block the conversion of PrP^C-PrP^Sc and increased effect on PrP^Sc clearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood–brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo.

Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrP^C-PrP^Sc.

Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrP^res in cell culture, inhibit the aggregation of a PrP^C peptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds.     

Synthesis,cytotoxic activity,and 2D‐ and 3D‐QSAR studies of 19‐carboxyl‐modified novel isosteviol derivatives as potential anticancer agents

Two series of novel acylthiosemicarbazide and oxadiazole fused‐isosteviol derivatives were synthesized based on the 19‐carboxyl modification. The target compounds were evaluated for their cytotoxicities against three cancer cell lines (HCT‐116, HGC‐27, and JEKO‐1) using an MTT assay. Lead compounds from the acylthiosemicarbazides ( 4 ) showed IC₅₀ values in the lower micromolar range. For example, compounds ( 4i , 4l , 4m , 4r, and 4s ) exhibited significant inhibitory activities against the three cell lines with IC₅₀ values of 0.95–3.36 μm . Furthermore, 2D‐HQSAR and 3D‐topomer CoMFA analyses were established, which could be used to develop second generation of isosteviol derivatives as anticancer agents.     

3D QSAR studies on cinnamaldehyde analogues as farnesyl protein transferase inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on 59 cinnamaldehyde analogues as Farnesyl Protein Transferase (FPTase) inhibitors were investigated using comparative molecular field analysis (CoMFA) with the PLS region-focusing method. Forty-nine training set inhibitors were used for CoMFA with two different grid spacings, 2A and 1A. Ten compounds, which were not used in model generation, were used to validate the CoMFA models. After the PLS analysis, the best predictive CoMFA model showed that the cross-validated value (r2cv) and the non-cross validated conventional value (r2ncv) are 0.557 and 0.950, respectively. From the CoMFA contour maps, the steric and electrostatic properties of cinnamaldehyde analogues can be identified and verified.     

阿片类药物透过血脑屏障的三维构效研究

目的:建立药物透过血脑屏障的三维构效模型,为药物分子设计提供理论依据。方法与结果:利用比较分子力场分析方法建立了阿片类药物透过血脑屏障的三维定量构效模型,该模型有较高的预测能力,交叉验证系数r²_cv=0.718,相关系数r²=0.978,F₃,7=67.902,标准偏差SE=0.209。结论:根据CoMFA模型系数等势图,解释了该类药物透过血脑屏障的构效关系。     

Pharmacophore-based 3D-QSAR of HIF-1 inhibitors

(Aryloxyamino)benzoic acids and nicotinic/isonicotinic acids represent an important new class of small molecules that inhibit the activation of Hypoxia-Inducible Factor (HIF)-1. In order to understand the factors affecting inhibitory potency of HIF-1 inhibitors, 3 dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed. Since no receptor structure are available, the pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models gave reasonable statistics (CoMFA: q² = 0.564, r²=0.945; CoMSIA: q² = 0.575, r²=0.929). Both CoMFA and CoMSIA results indicate that the steric interaction is a major factor, while CoMSIA suggests importance of hydrogen bonding. These findings about steric and H-bonding effects can be useful to design new inhibitors. Equally contributed in this work.     

In silico identification of anthropogenic chemicals as ligands of zebrafish sex hormone binding globulin

Anthropogenic compounds with the capacity to interact with the steroid-binding site of sex hormone binding globulin (SHBG) pose health risks to humans and other vertebrates including fish. Building on studies of human SHBG, we have applied in silico drug discovery methods to identify potential binders for SHBG in zebrafish (Danio rerio) as a model aquatic organism. Computational methods, including; homology modeling, molecular dynamics simulations, virtual screening, and 3D QSAR analysis, successfully identified 6 non-steroidal substances from the ZINC chemical database that bind to zebrafish SHBG (zfSHBG) with low-micromolar to nanomolar affinities, as determined by a competitive ligand-binding assay. We also screened 80,000 commercial substances listed by the European Chemicals Bureau and Environment Canada, and 6 non-steroidal hits from this in silico screen were tested experimentally for zfSHBG binding. All 6 of these compounds displaced the [³H]5α-dihydrotestosterone used as labeled ligand in the zfSHBG screening assay when tested at a 33 μM concentration, and 3 of them (hexestrol, 4-tert-octylcatechol, and dihydrobenzo(a)pyren-7(8H)-one) bind to zfSHBG in the micromolar range. The study demonstrates the feasibility of large-scale in silico screening of anthropogenic compounds that may disrupt or highjack functionally important protein:ligand interactions. Such studies could increase the awareness of hazards posed by existing commercial chemicals at relatively low cost.     

烯丙胺类抗真菌药物比较分子力场分析(CoMFA)的研究

本实验采用“活性类似物法”确定了烯丙胺类抗真菌化合物的药效构象,采用比较分子力场分析法(CoMFA)拟合了48个烯丙胺类抗真菌化合物对6种常见致病真菌的3D-QSAR方程,并比较了2种不同叠合规则对模型的影响,最后,用5个新合成化合物对所拟合的抗石膏样毛癣菌、抗烟曲霉菌的CoMFA模型的预测能力进行了检验,得到比较满意的结果。     

三唑杀菌剂的三维定量构效关系研究

利用限制性构象搜寻确定了三唑杀菌剂１３个化合物的重叠规则，并利用比较分子力场分析方法进行了三维定量构效关系（ＱＳＡＲ）研究。得到具有较强预测能力的ＱＳＡＲ模型，研究结果表明：影响此类化合物生物活性的主要是空间立体效应，而是勺为次要因素，并依据模型设计出了高活性的化合物。