Combined Molecular Docking, 3D‐QSAR,and Pharmacophore Model: Design of Novel Tubulin Polymerization Inhibitors by Binding to Colchicine‐binding Site

Interference with dynamic equilibrium of microtubule–tubulin has proven to be a useful tactics in the clinic. Based on investigation into the structure–activity relationship (SAR) studies of tubulin polymerization inhibitors obtained from several worldwide groups, we attempted to design 691 compounds covering several main heterocyclic scaffolds as novel colchicine‐site inhibitors (CSIs). Evaluated by a series of combination of commonly used computer methods such as molecular docking, 3D‐QSAR, and pharmacophore model, we can obtain the ultimate 16 target compounds derived from five important basic scaffolds in the field of medicinal chemistry. Among these compounds, compound A‐132 with in silico moderate activity was synthesized, and subsequently validated for preliminary inhibition of tubulin polymerization by immunofluorescence assay. In additional, the work of synthesis and validation of biological activity for other 15 various structure compounds will be completed in our laboratory. This study not only developed a hierarchical strategy to screen novel tubulin inhibitors effectively, but also widened the spectrum of chemical structures of canonical CSIs.     

Ligand-based Pharmacophore Modeling; Atom-based 3D-QSAR Analysis and Molecular Docking Studies of Phosphoinositide-Dependent Kinase-1 Inhibitors

Phosphoinositide-dependent kinase-1 plays a vital role in the PI3-kinase signaling pathway that regulates gene expression, cell cycle growth and proliferation. The common human cancers include lung, breast, blood and prostate possess over stimulation of the phosphoinositide-dependent kinase-1 signaling and making phosphoinositide-dependent kinase-1 an interesting therapeutic target in oncology. A ligand-based pharmacophore and atom-based 3D-QSAR studies were carried out on a set of 82 inhibitors of PDK1. A six point pharmacophore with two hydrogen bond acceptors (A), three hydrogen bond donors (D) and one hydrophobic group (H) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least square statistics results. The training set correlation is characterized by partial least square factors (R² = 0.9557, SD = 0.2334, F = 215.5, P = 1.407e-32). The test set correlation is characterized by partial least square factors (Q² ext = 0.7510, RMSE = 0.5225, Pearson-R =0.8676). The external validation indicated that our QSAR model possess high predictive power with good value of 0.99 and value of 0.88. The docking results show the binding orientations of these inhibitors at active site amino acid residues (Ala162, Thr222, Glu209 and Glu166) of phosphoinositide-dependent kinase-1 protein. The binding free energy interactions of protein-ligand complex have been calculated, which plays an important role in molecular recognition and drug design approach.     

General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.     

Molecular Docking and 3D QSAR Studies of Chk2 Inhibitors

Isothiazole‐carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three‐dimensional quantitative structure–activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method‐1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand‐based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor‐guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule‐7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method‐2 and 3. These methods were used for 3D QSAR. The geometrical method‐3‐based comparative molecular field analysis (q ² = 0.75, r ² = 0.87 and r ²_predict = 0.81) and comparative molecular similarity indices analysis (q ² = 0.90, r ² = 0.96 and r ²_predict = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor‐guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.     

Synthesis, structure-activity relationship, and pharmacophore modeling studies of pyrazole-3-carbohydrazone derivatives as dipeptidyl peptidase IV inhibitors

Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.     

First pharmacophore model of CCR3 receptor antagonists and its homology model-assisted, stepwise virtual screening

CCR3, a G protein-coupled receptor, plays a central role in allergic inflammation and is an important drug target for inflammatory diseases. To understand the structure-function relationship of CCR3 receptor, different computational techniques were employed, which mainly include: (i) homology modeling of CCR3 receptor, (ii) 3D-quantitative pharmacophore model of CCR3 antagonists, (iii) virtual screening of small compound databases, and (iv) finally, molecular docking at the binding site of the CCR3 receptor homology model. Pharmacophore model was developed for the first time, on a training data set of 22 CCR3 antagonists, using CATALYST HypoRefine program. Best hypothesis (Hypo1) has three different chemical features: two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic. Hypo1 model was further validated using (i) 87 test set CCR3 antagonists, (ii) Cat Scramble randomization technique, and (iii) Decoy data set. Molecular docking studies were performed on modeled CCR3 receptor using 303 virtually screened hits, obtained from small compound database virtual screening. Finally, five hits were identified as potential leads against CCR3 receptor, which exhibited good estimated activities, favorable binding interactions, and high docking scores. These studies provided useful information on the structurally vital residues of CCR3 receptor involved in the antagonist binding, and their unexplored potential for the future development of potent CCR3 receptor antagonists.     

Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling,Atom‐Based 3D‐QSAR and Docking Studies

Formylchromane derivatives were reported to possess irreversible and selective inhibition on human protein tyrosine phosphatase 1B (PTP 1B). Inhibition of PTP 1B is a molecular level legitimate approach for the management of type 2 diabetes mellitus (T2DM). 3D‐QSAR studies were performed on a series of formylchromane derivatives using partial least square (PLS) analysis for correlating molecular architecture of the analogs with their PTP 1B inhibitory activity. A five‐point pharmacophore hypothesis with three hydrogen bond acceptors (A) and two aromatic rings (R) as pharmacophoric features was developed using phase module of Schrödinger suite. The hypothesis AAARR.160 was considered as best hypothesis in this study characterized by survival score (3.483), the best cross‐validated r² (Q²) (0.774), regression coefficient (0.960), Pearson‐R (0.891), and F value (100.3). The results of hypothesis AAARR.160 complimented very closely to interactions witnessed in active site of the ligand‐bound complex. The molecular docking simulations into PTP 1B active site also highlighted that biphenyl moiety favorably interacted with amino acid residues lining the lipophilic pocket, and provided hydrophobic interactions with receptor active site. These observations might be useful for further development and optimization of new chemical entities as potential PTP 1B inhibitors prior to its synthesis.     

Identification of novel polo-like kinase 1 inhibitors by a hybrid virtual screening

Polo-like kinase 1 is an important and attractive oncological target that plays a key role in mitosis and cytokinesis. A combined pharmacophore- and docking-based virtual screening was performed to identify novel polo-like kinase 1 inhibitors. A total of 34 hit compounds were selected and tested in vitro, and some compounds showed inhibition of polo-like kinase 1 and human tumor cell growth. The most potent compound (66) inhibited polo-like kinase 1 with an IC(50) value of 6.99 μm. The docked binding models of two hit compounds were discussed in detail. These compounds contained novel chemical scaffolds and may be used as foundations for the development of novel classes of polo-like kinase 1 inhibitors.     

Identification of Dipeptidyl Peptidase IV Inhibitors: Virtual Screening,Synthesis and Biological Evaluation

Inhibition of dipeptidyl peptidase IV is an important approach for the treatment of type‐2 diabetes. In this study, we reported a multistage virtual screening workflow that integrated 3D pharmacophore models, structural consensus docking, and molecular mechanics/generalized Born surface area binding energy calculation to identify novel dipeptidyl peptidase IV inhibitors. After screening our in‐house database, two hit compounds, HWL‐405 and HWL‐892, having persistent high performance in all stages of virtual screening were identified. These two hit compounds together with several analogs were synthesized and evaluated for in vitro inhibition of dipeptidyl peptidase IV. The experimental data indicated that most designed compounds exhibited significant dipeptidyl peptidase IV inhibitory activity. Among them, compounds 35f displayed the greatest potency against dipeptidyl peptidase IV in vitro with the IC₅₀ value of 78 nm . In an oral glucose tolerance test in normal male Kunming mice, compound 35f reduced blood glucose excursion in a dose‐dependent manner.     

On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein

SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray of 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led to identification of only eight sequences as potent antagonists; results that were supported by detailed dual-filter computational studies. Competitive studies using the HS microarray suggested almost equivalent importance of IdoA2S–GlcNS6S and GlcNS3S structures, which were supported by affinity studies. Exhaustive virtual screening on a library of >93 000 sequences led to a novel pharmacophore with at least two 3-O-sulfated GlcN residues that can engineer unique selectivity in recognizing the RBD. This work puts forward the key structural motif in HS that should lead to potent and selective HS or HS-like agents against SARS-CoV-2.     

病毒3CL蛋白酶三维结构模型及其抑制剂的虚拟筛选(英文)

目的:构建SARS病毒类3C(3CL)蛋白酶的三维结构模型,根据这一模型设计3CL蛋白酶的抑制剂。方法:用生物信息学方法从GenBank和PDB库中搜寻出具有晶体结构并与SARS病毒3CL蛋白酶有较高同源型的蛋白质,以此为模板,用同源蛋白模建方法构建SARS病毒3CL蛋白酶的三维结构模型;针对模建的三维结构模型,进行高通量虚拟筛选,从现有小分子数据库中获得具有抑制SARS病毒3CL蛋白酶活性的化合物。结果:同源性分析表明SARS病毒3CL蛋白酶与遗传性肠胃炎主蛋白酶(TGEV M~(pro)),有较高的同源性,组成底物结合口袋残基的同源性更高。因此,可以根据TGEV M~(pro)的晶体结构为模板模建SARS病毒3CL蛋白酶的三维结构。 三维结构模型表明,ARS病毒3CL蛋白酶的结构与TGEV M~(pro)的结构非常相象,两个蛋白酶活性口袋的结构和形状儿乎一样。虚拟筛选测试研究表明,MRRD数据库中的73个蛋白酶抑制剂能与两个蛋白同时作用。结论:无论是SARS病毒3CL蛋白酶还是TGEV M~(pro)的晶体结构均可以作为设计抗SARS药物的结构模型。从现有的蛋白酶抑制剂中筛选抗SARS药物可能是一条好的途径。     

Pharmacophore modeling, 3D-QSAR,synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC₅₀ values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine ( 6b ) achieved the highest cytotoxic activity against H1299 with an IC₅₀ value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC₅₀ value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b , gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

Computational Inhibition Studies of the Human Proteasome by Argyrin‐Based Analogues with Subunit Specificity

A computational procedure was developed to study the subunit‐specific interactions of the proteasome inhibitors argyrin A and F, with the aim of indentifying the determinants of subunit selectivity. Three‐dimensional models of humanized proteasome active sites β₁, β₂ and β₅ were developed and subsequently used in molecular docking simulations with the argyrin analogues. The subunit selectivity exhibited by each analogue could be explained based on the site‐specific interactions and a probability‐based specificity parameter derived in this study. A rational approach that involved maximizing site‐specific interactions was followed to guide the design of new argyrin analogues as specific inhibitors of the caspase‐like (β₁ site) activity.     

Shape- and Chemical Feature-Based 3D-Pharmacophore Model Generation and Virtual Screening: Identification of Potential Leads for P. falciparum DHFR Enzyme Inhibition

Plasmodium falciparum dihydrofolate reductase (Pf DHFR) enzyme is one of the validated targets in the treatment of malaria using typical antifolates such as cycloguanil and pyrimethamine. However, point mutations at amino acid residues such as Ala16, Ile51, Cys59, Ser108 and Ile164 in the active site of the wild-type enzyme resulted in a widespread resistance of the parasite to these drugs. Thus, design and discovery of new potential Pf DHFR inhibitors, equally active against both the wild-type and mutant strains, is an urgent need. Catalyst software was used to generate a 3D pharmacophore query based on the bioactive conformation of WR99210 extracted from the X-ray crystal structure of quadruple mutant PfDHFR enzyme. Validation criteria based on the experimentally determined conformation of WR99210 and its key interactions with the protein were considered to identify hits from two chemical databases, namely, NCI2000 and Maybridge2004 using different virtual filters. Virtual screening based on FlexX, GOLD and Glide docking programs resulted in a total of 73 hits. The hits reported in this article showed good potential to be inhibitors of the above Pf DHFRs based on their (i) best-fit values (ii) binding scores (iii) binding modes and (iv) interactions with the key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14).     

Identification of Vitamin D3-Based Hedgehog Pathway Inhibitors That Incorporate an Aromatic A-Ring Isostere

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