Synthesis,characterization, density functional theory,X‐ray study,thermal stability,and biological and MOE relevance of metal complexes of griseofulvin

Metal(II) and metal(III) coordination compounds of griseofulvin (GFV) drug were synthesized. The structure of the ligand was determined on the basis of elemental analyses, infrared and ¹H NMR spectroscopies and thermal studies. GFV behaved as a neutral tridentate chelating agent and coordinated to metal ions through three oxygen atoms: two methoxy groups and oxygen atom of furan ring. Metal complexes were characterized by means of elemental analyses and molar conductance, spectral (infrared, electron spin resonance) and thermal studies. All the complexes showed molar conductance behaviour corresponding to an electrolytic nature. All the complexes showed octahedral geometry, except [Zn(GFV)Cl]Cl that showed tetrahedral geometry. Density functional theory (DFT) calculations were employed to understand and estimate the contribution of each interaction in the formation of the assembly using several theoretical models. The computed parameters from DFT calculations for structure optimizations and vibrational frequencies were in good agreement with the experimental data. Newly synthesized metal complexes in addition to GFV were examined against opportunistic pathogens. The biological applications of complexes were studied with two Gram‐positive bacteria (Bacillus subtilis and Staphylococcus aureus) and two Gram‐negative bacteria (Escherichia coli and Neisseria gonorrhoeae) as well as their antifungal activity against Candida albicans. Results suggested that metal complexes were more biologically sensitive than free ligand. The complexes showed a moderate inhibition of MCF7 breast cancer cell line growth. Molecular docking studies further helped in understanding the mode of action of the compounds through their various interactions with the crystal structures of: human serum albumin (PDB: 5FUO), Staphylococcus aureus nucleoside (PDB: 3Q8U), human acetylcholinesterase (PDB: 1B41) and the human DNA–Topo I complex (PDB: 1SC7).     

基于酸度诱导的HSA与BDE154的光谱和计算模拟研究

在不同酸度条件下（pH＝3.0，6.0，7.4，9.0）诱导人血清白蛋白（HSA）进行质子化或去质子化，以研究其与小分子2，2'，4，4'，5，6'-六溴联苯醚（BDE154）的结合情况.首先将HSA与BDE154进行半柔性对接，发现BDE154与HSA周围的残基，如：酪氨酸150、赖氨酸195、赖氨酸199等存在较强的疏水相互作用.然后通过分子动力学模拟技术研究HSA在不同质子化状态下的动力学行为和热力学性质，可知过多的正电荷使HSA或者HSA-BDE154的系统稳定性变差.最后对HSA-BDE154的结合自由能进行预测，并对分子动力学模拟结果进行二级结构分析，结果表明HSA-BDE154复合物体系中随着酸度的增大，配体的结合对HSA的去螺旋过程有促进的作用.     

鲍曼不动杆菌LpxC的同源模建及分子对接

鲍曼不动杆菌已成为最普遍的医院致病菌,且耐药情况严峻.LpxC作为新抗菌药物靶点被大量研究,但鲍曼不动杆菌LpxC晶体尚未解析得到,基于其结构的药物设计等工作无法开展.以铜绿假单胞菌LpxC晶体结构为模板,通过同源模建方法获得鲍曼不动杆菌LpxC结构模型.较好的Ramachandran plot分布和Profile-3D结果验证了模型的合理性.用分子动力学模拟优化鲍曼不动杆菌LpxC模型,修补部分不合理构象.后续分子对接结果显示S构型的苄氧乙酰基羟肟酸类抑制剂比R构型分子能更有效地结合在F191,H237和K238组成的较浅口袋中,这可能是S构型抑制剂活性更高的主要因素,模拟结果与实验数据吻合较好.     

Fast and accurate grid representations for atom‐based docking with partner flexibility

Macromolecular docking methods can broadly be divided into geometric and atom‐based methods. Geometric methods use fast algorithms that operate on simplified, grid‐like molecular representations, while atom‐based methods are more realistic and flexible, but far less efficient. Here, a hybrid approach of grid‐based and atom‐based docking is presented, combining precalculated grid potentials with neighbor lists for fast and accurate calculation of atom‐based intermolecular energies and forces. The grid representation is compatible with simultaneous multibody docking and can tolerate considerable protein flexibility. When implemented in our docking method ATTRACT, grid‐based docking was found to be ∼35x faster. With the OPLSX forcefield instead of the ATTRACT coarse‐grained forcefield, the average speed improvement was >100x. Grid‐based representations may allow atom‐based docking methods to explore large conformational spaces with many degrees of freedom, such as multiple macromolecules including flexibility. This increases the domain of biological problems to which docking methods can be applied. © 2017 Wiley Periodicals, Inc.     

Urea and thiourea derivatives of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine: Synthesis,characterization, antimicrobial activity and docking studies

Abstract

An efficient and robust synthetic procedure was developed primarily for the synthesis of a precursor compound; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine (11), from 2-chloropyrazine (7) through the chemical transformations such as hydrazine substitution, trifluoroacetyl group induction, cyclization and pyrazine ring reduction. A new series of urea derivatives 13a-e and thiourea derivatives 13f-j of compound 11 have been synthesized and the structures of all the compounds were confirmed using spectroscopic analyses such as IR, ¹H NMR, ¹³C NMR, LC-MS and HRMS. The newly synthesized compounds were screened for their in vitro antimicrobial activity against five bacteria and two fungi, in which compounds 13d, 13i and 13j displayed potential activity against bacterial strains and 13a, 13d, 13g and 13j against fungal strains with the MIC values in the range of 6.25–25.0 µg/mL. An overall comparison of the activity results revealed that thiourea derivatives contain better activity than that of urea compounds. Molecular docking studies on poly (ADP-ribose) polymerase 15 (ARTD7, BAL3) demonstrated that all the synthesized compounds possess significant binding energies (-8.1 to -9.8?kcal/mol) with no adverse effect in the active site of protein.     

Identification of potential HIV-1 integrase strand transfer inhibitors: In silico virtual screening and QM/MM docking studies

HIV-1 integrase (IN) is a retroviral enzyme that catalyses integration of the reverse-transcribed viral DNA into the host genome, which is necessary for efficient viral replication. In this study, we have performed an in silico virtual screening for the identification of potential HIV-1 IN strand transfer (ST) inhibitors. Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to 3-Hydroxypyrimidine-2,4-diones. Based on the ligand-based pharmacophore model, we obtained a five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H) and one aromatic ring (R) as pharmacophoric features. The pharmacophore hypothesis AADHR was used as a 3D query in a sequential virtual screening study to filter small molecule databases Maybridge, ChemBridge and Asinex. Hits matching with pharmacophore hypothesis AADHR were retrieved and passed progressively through Lipinski’s rule of five filtering, molecular docking and hierarchical clustering. The five compounds with best hits with novel and diverse chemotypes were subjected to QM/MM docking, which showed improved docking accuracy. We further performed molecular dynamics simulation and found three compounds that form stable interactions with key residues. These compounds could be used as a leads for further drug development and rational design of HIV-1 IN inhibitors.     

Theory of docking scores and its application to a customizable scoring function

In general, the docking scoring tends to have a size dependence related to the ranking of compounds. In this paper, we describe a novel method of parameter optimization for docking scores which reduce the size dependence and can efficiently discriminate active compounds from chemical databases. This method is based on a simplified theoretical model of docking scores which enables us to utilize large amounts of data of known active and inactive compounds for a particular target without requiring large computational resources or a complicated procedure. This method is useful for making scoring functions for the identification of novel scaffolds using the knowledge of active compounds for a particular target or a customized scoring function for an interesting family of drug targets.     

Pharmacophore modelling,molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r _training?=?0.89, r _test?=?0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.     

Analysis of Ah receptor binding affinities of polybrominated diphenyl ethers via in silico molecular docking and 3D-QSAR

Polybrominated diphenyl ethers (PBDEs) have become ubiquitous contaminations due to their use as flame retardants. The structural similarity of PBDE to some dioxin-like compounds suggested that they may share similar toxicological effects: they might activate the aryl hydrocarbon receptor (AhR) signal transduction pathway and thus might have adverse effects on wildlife and humans. In this study, in silico computational workflow combining molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) was performed to investigate the binding interactions between PBDEs and AhR and the structural features affecting the AhR binding affinity of PBDE. The molecular docking showed that hydrogen-bond and hydrophobic interactions were the major driving forces for the binding of ligands to AhR, and several key amino acid residues were also identified. The CoMSIA model was developed from the conformations obtained from molecular docking and exhibited satisfactory results as q ² of 0.605 and r ² of 0.996. Furthermore, the derived model had good robustness and statistical significance in both internal and external validations. The 3D contour maps generated from CoMSIA provided important structural features influence the binding affinity. The obtained results were beneficial to better understand the toxicological mechanism of PBDEs.     

Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity

Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.