A new glimpse on the active site of SARS-CoV-2 3CLpro,coupled with drug repurposing study

Molecular Diversity - Coronavirus disease 2019 (COVID-19) is caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2). Its main protease, 3C-like protease (3CLpro), is an...     

糖原合酶激酶3(GSK3)介导的胰岛素对糖原 合酶2(GYS2)的抑制调节

本文基于Hill 动力学与 Michaelis-Menten 方程,建立理论模型研究肝癌(HCC)进展过程的微环境中,糖原合酶激酶3(GSK3)介导的胰岛素对糖原代谢的抑制调节,以及 P53 蛋白恢复调节糖原代谢异常的作用。分析了胰岛素激活 AKT 激酶影响 GYS2 磷酸化/去磷酸化转变的昼夜节律性,以及 P53 通过抑制 AKT,对 GYS2 磷酸化/去磷酸化转变的昼夜节律性异常的调节恢复特性。研究发现,胰岛素激活并提升 AKT 的表达水平,经过 AKT 的催化作用,GSK3 的表达被抑制减弱,进而增强了 GYS2 的磷酸化和失活。在胰岛素浓度较低的情况下,GYS2 去磷酸化激活的昼夜节律性会被改变,进而改变了 GYS2 昼夜节律的合成规律。在较高胰岛素浓度条件下,去磷酸化的 GYS2(dGYS2) 随时间演变的周期振荡性会被极大地改变,GYS2 昼夜节律的合成规律被破坏。改变 P53 的表达水平,我们发现,P53 对较低和较高胰岛素浓度条件下 dGYS2 异常的昼夜节律演化性,有明显的调节恢复作用。通过 P53 的调节,dGYS 随时间演化异常紊乱的昼夜节律性被还原,GYS2 恢复昼夜节律的合成。理论结果符合实验,并进一步分析了 GSK3 介导的胰岛素调节 GYS2 磷酸化/去磷酸化转变的昼夜节律性的调节机理,以及 P53 对GYS2 磷酸化/去磷酸化转变异常的调节恢复特性,进而揭示了 HCC 发生发展的一种致癌、抑癌机理,可为设计阻断致癌转变的通路治疗方案提供理论依据。     

Structure-based drug design,synthesis and screening of MmaA1 inhibitors as novel anti-TB agents

Molecular Diversity - Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces...     

Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach

JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 ( $Q_{\mathrm{test}}^{2} 0.663, R^{2}_{\mathrm{train}} 0.849$ , F value 219.3) for JAK2 and ADDRR.142 ( $Q^{2}_{\mathrm{test}}0.655, R_{\mathrm{train}}^{2}$ 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.     

Discovery and identification of PIM-1 kinase inhibitors through a hybrid screening approach

PIM-1 kinase is an important therapeutic target in the treatment of cancer. Discovery and identification of PIM-1 Inhibitors with novel scaffolds are an effective way for developing potent therapeutic agents for the treatment of cancers. Here we proposed a hybrid screening approach which combines an optimal structure-based drug design strategy and a simple pharmacophore model to discover PIM-1 kinase inhibitors. With the proposed hybrid screening approach, the SPECS database containing 204,580 molecules was screened. In total, 89 hits were obtained. Forty three of them were purchased and tested in bioassays. Finally, 5 lead compounds with novel scaffolds were identified to exhibit promising antitumor activities against human leukemia cell line MV4-11, K-562 and human prostate cancer cell line PC-3 and DU145. Their $\hbox {IC}_{50}$ values range from 4.40 to $37.96 \,\upmu \hbox {M}$ . Three hits with 3 different scaffolds were selected from these five hits for binding mode analysis. It was demonstrated that the subtle differences in the interactions of the representatives with PIM-1 kinase contribute to the different inhibitory activities. It was also demonstrated that the suggested hybrid screening approach is an effective method to discover PIM-1 inhibitors possessing different scaffolds. These leads have a strong likelihood to act as further starting points for us in the optimization and development of potent PIM-1 inhibitors.     

Combinatorial chemistry and high-throughput screening in drug discovery: Different strategies and formats

Different strategies for the discovery of novel leadsinteracting with therapeutically relevant targets are thoroughlypresented and discussed, using also three recent examples.Emphasis is given to approaches which do not require extensiveresources and budgets, but rather prove how cleverness andcreativity can provide active compounds in drug discovery.     

2D-SAR and 3D-QSAR analyses for acetylcholinesterase inhibitors

Alzheimer’s disease (AD) accounts for almost three quarters of dementia patients and interferes people’s normal life. Great progress has been made recently in the study of Acetylcholinesterase (AChE), known as one of AD’s biomarkers. In this study, acetylcholinesterase inhibitors (AChEI) were collected to build a two-dimensional structure–activity relationship (2D-SAR) model and three-dimensional quantitative structure–activity relationship (3D-QSAR) model based on feature selection method combined with random forest. After calculation, the prediction accuracy of the 2D-SAR model was 89.63% by using the tenfold cross-validation test and 87.27% for the independent test set. Three cutting ways were employed to build 3D-QSAR models. A model with the highest \({q}^{2}\) (cross-validated correlation coefficient) and \({r}^{2 }\)(non-cross-validated correlation coefficient) was obtained to predict AChEI activity. The mean absolute error (MAE) of the training set and the test set was 0.0689 and 0.5273, respectively. In addition, molecular docking was also employed to reveal that the ionization state of the compounds had an impact upon their interaction with AChE. Molecular docking results indicate that Ser124 might be one of the active site residues.     

Synthesis,characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents

Thymidylate synthase (TS), one of folate-dependent enzymes, is a key and well-recognized target for anticancer agents. In this study, a series of 6-aryl-5-cyano thiouracil derivatives were designed and synthesized in accordance with essential pharmacophoric features of known TS inhibitors. Nineteen compounds were screened in vitro for their anti-proliferative activities toward HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Compounds \(\mathbf{21}_{\mathbf{c}}\), \(\mathbf{21}_{\mathbf{d}}\), and 24 exhibited high anti-proliferative activity, comparable to that of 5-fluorouracil. Additionally, ten compounds with potent anti-proliferative activities were further evaluated for their ability to inhibit TS enzyme. Six compounds (\(\mathbf{21}_{\mathbf{b}}\), \(\mathbf{21}_{\mathbf{c}}\), \(\mathbf{21}_{\mathbf{d}}\), 22, 23 and 24) demonstrated potent dose-related TS inhibition with \(\hbox {IC}_{50}\) values ranging from 1.57 to \(3.89\,\upmu \hbox {M}\). The in vitro TS activity results were consistent with those of the cytotoxicity assay where the most potent anti-proliferative compounds of the series showed good TS inhibitory activity comparable to that of 5-fluorouracil. Furthermore, molecular docking studies were carried out to investigate the binding pattern of the designed compounds with the prospective target, TS (PDB-code: 1JU6).     

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening,molecular docking,ADMET analysis and MD simulations

Molecular Diversity - In the absence of efficient anti-viral medications, the coronavirus disease 2019 (COVID-19), stemming from severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), has...     

Identification of dual Acetyl-CoA carboxylases 1 and 2 inhibitors by pharmacophore based virtual screening and molecular docking approach

Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme that plays a vital role in obesity-induced type 2 diabetes and fatty acid metabolism. To identify dual inhibitors of Acetyl-CoA carboxylase1 and Acetyl-CoA carboxylase2, a pharmacophore modelling approach has been employed. The best HypoGen pharmacophore model for ACC2 inhibitors (Hypo1_ACC2) consists of one hydrogen bond acceptor, one hydrophobic aliphatic and one hydrophobic aromatic feature, whereas the best pharmacophore (Hypo1_ACC1) for ACC1 consists of one additional hydrogen-bond donor (HBD) features. The best pharmacophore hypotheses were validated by various methods such as test set, decoy set and Cat-Scramble methodology. The validated pharmacophore models were used to screen several small-molecule databases, including Specs, NCI, ChemDiv and Natural product databases to identify the potential dual ACC inhibitors. The virtual hits were then subjected to several filters such as estimated $\text{ IC}_{50}$ value, quantitative estimation of drug-likeness and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as potential starting points for the design of novel dual ACC inhibitors.     

Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening

A glutaminyl cyclase (QC) fragment library was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screening of the same set. The resulting fragment library (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragment hits were identified (\(\sim \)5 % hit rate, best inhibitory activity: 16 \(\upmu \hbox {M}\)). The in vitro hits were then docked to the active site of QC, and the best scoring compounds were analyzed for binding interactions. Two fragments bound to different regions in a complementary manner, and thus, linking those fragments offered a rational strategy to generate novel QC inhibitors. Based on the structure of the virtual linked fragment, a 77-membered QC target focused library was selected from vendor databases and docked to the active site of QC. A PubChem search confirmed that the best scoring analogues are novel, potential QC inhibitors.     

Identifying potential inhibitors of biofilm-antagonistic proteins to promote biofilm formation: a virtual screening and molecular dynamics simulations approach

Molecular Diversity - Microbial biofilms play a critical role in environmental biotechnology and associated applications. Biofilm production can be enhanced by inhibiting the function of proteins...