A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure–activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

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Towards further Understanding the Structural Requirements of Combretastatin- like Chalcones as Inhibitors of Microtubule Polymerization

Current Computer - Aided Drug Design ◽

10.2174/1573409915666181221114107 ◽

2020 ◽

Vol 16 (2) ◽

pp. 155-166

Author(s):

Naveen Dhingra ◽

Anand Kar ◽

Rajesh Sharma

Keyword(s):

Three Dimensional ◽

3D Qsar ◽

Docking Study ◽

Structure Activity Relationship ◽

Docking Studies ◽

Activity Relationship ◽

Structural Requirement ◽

Ligand Interaction ◽

Microtubule Polymerization ◽

Structure Activity

Background: Microtubules are dynamic filamentous cytoskeletal structures which play several key roles in cell proliferation and trafficking. They are supposed to contribute in the development of important therapeutic targeting tumor cells. Chalcones are important group of natural compounds abundantly found in fruits & vegetables that are known to possess anticancer activity. We have used QSAR and docking studies to understand the structural requirement of chalcones for understanding the mechanism of microtubule polymerization inhibition. Methods: Three dimensional (3D) QSAR (CoMFA and CoMSIA), pharmacophore mapping and molecular docking studies were performed for the generation of structure activity relationship of combretastatin-like chalcones through statistical models and contour maps. Results: Structure activity relationship revealed that substitution of electrostatic, steric and donor groups may enhance the biological activity of compounds as inhibitors of microtubule polymerization. From the docking study, it was clear that compounds bind at the active site of tubulin protein. Conclusion: The given strategies of modelling could be an encouraging way for designing more potent compounds as well as for the elucidation of protein-ligand interaction.

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Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.4.947 ◽

1996 ◽

Vol 40 (4) ◽

pp. 947-952 ◽

Cited By ~ 40

Author(s):

H L Callahan ◽

C Kelley ◽

T Pereira ◽

M Grogl

Keyword(s):

Leishmania Major ◽

Leishmania Species ◽

Significant Activity ◽

Topical Formulation ◽

Microtubule Inhibitor ◽

Microtubule Inhibitors ◽

Structure Activity ◽

Putative Mechanism

Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.

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HAZARD: An Expert System for Risk Assessment of Environmental Chemicals

Methods of Information in Medicine ◽

10.1055/s-0038-1635482 ◽

1987 ◽

Vol 26 (01) ◽

pp. 13-23 ◽

Cited By ~ 2

Author(s):

H. W. Gottinger

Keyword(s):

Expert System ◽

Structural Information ◽

Chemical Carcinogenesis ◽

Structural Features ◽

Environmental Chemicals ◽

Chemical Carcinogens ◽

Carcinogenic Activity ◽

Current State ◽

Structure Activity ◽

Carcinogenic Potential

AbstractThe purpose of this paper is to report on an expert system in design that screens for potential hazards from environmental chemicals on the basis of structure-activity relationships in the study of chemical carcinogenesis, particularly with respect to analyzing the current state of known structural information about chemical carcinogens and predicting the possible carcinogenicity of untested chemicals. The structure-activity tree serves as an index of known chemical structure features associated with carcinogenic activity. The basic units of the tree are the principal recognized classes of chemical carcinogens that are subdivided into subclasses known as nodes according to specific structural features that may reflect differences in carcinogenic potential among chemicals in the class. An analysis of a computerized data base of known carcinogens (knowledge base) is proposed using the structure-activity tree in order to test the validity of the tree as a classification scheme (inference engine).

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Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

10.26434/chemrxiv.12026952 ◽

2020 ◽

Author(s):

Luke Adams ◽

Lorna E. Wilkinson-White ◽

Menachem J. Gunzburg ◽

Stephen J. Headey ◽

Martin J. Scanlon ◽

...

Keyword(s):

Binding Site ◽

Systematic Approach ◽

Structural Information ◽

Peptide Binding ◽

Chemical Diversity ◽

Chemical Probes ◽

Protein Targets ◽

Structure Activity ◽

Peptide Binding Site ◽

Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

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Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

Current Drug Discovery Technologies ◽

10.2174/1570163815666181008165822 ◽

2020 ◽

Vol 17 (2) ◽

pp. 233-247

Author(s):

Krishna A. Gajjar ◽

Anuradha K. Gajjar

Keyword(s):

Molecular Docking ◽

Structural Information ◽

Docking Studies ◽

Structural Motif ◽

Roc Curve Analysis ◽

Ligand Complex ◽

Discovery Studio ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Pharmacophore Models

Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

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Development of Novel Glitazones as Antidiabetic Agents: Molecular Design, Synthesis, Evaluation of Glucose Uptake Activity and SAR Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180816666191105124535 ◽

2020 ◽

Vol 17 (7) ◽

pp. 840-849

Author(s):

Mahendra Gowdru Srinivas ◽

Prabitha Prabhakaran ◽

Subhankar Probhat Mandal ◽

Yuvaraj Sivamani ◽

Pranesh Guddur ◽

...

Keyword(s):

Glucose Uptake ◽

Molecular Design ◽

Docking Studies ◽

Antidiabetic Activity ◽

Design Synthesis ◽

In Silico Docking ◽

Ppar Γ ◽

Sar Studies ◽

Structure Activity ◽

Uptake Activity

Background: Thiazolidinediones and its bioisostere, namely, rhodanines have become ubiquitous class of heterocyclic compounds in drug design and discovery. In the present study, as part of molecular design, a series of novel glitazones that are feasible to synthesize in our laboratory were subjected to docking studies against PPAR-γ receptor for their selection. Methods and Results: As part of the synthesis of selected twelve glitazones, the core moiety, pyridine incorporated rhodanine was synthesized via dithiocarbamate. Later, a series of glitazones were prepared via Knovenageal condensation. In silico docking studies were performed against PPARγ protein (2PRG). The titled compounds were investigated for their cytotoxic activity against 3T3-L1 cells to identify the cytotoxicity window of the glitazones. Further, within the cytotoxicity window, glitazones were screened for glucose uptake activity against L6 cells to assess their possible antidiabetic activity. Conclusion: Based on the glucose uptake results, structure activity relationships are drawn for the title compounds.

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Structure Activity Relationship of Arylidene Pyrrolo and Pyrido [2,1-b] Quinazolones as Cytotoxic Agents: Synthesis, SAR Studies, Biological Evaluation and Docking Studies

Medicinal Chemistry ◽

10.2174/1573406411309050003 ◽

2013 ◽

Vol 9 (5) ◽

pp. 642-650 ◽

Cited By ~ 3

Author(s):

Veenu Mangla ◽

Kunal Nepali ◽

Gagandip Singh ◽

Jagjeet Singh ◽

Santosh Guru ◽

...

Keyword(s):

Structure Activity Relationship ◽

Docking Studies ◽

Biological Evaluation ◽

Cytotoxic Agents ◽

Activity Relationship ◽

Sar Studies ◽

Structure Activity ◽

Relationship Of

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Recent Development of Sulfonyl or Sulfonamide Hybrids as Potential Anticancer Agents: A Key Review

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666171103140749 ◽

2018 ◽

Vol 18 (4) ◽

pp. 488-505 ◽

Cited By ~ 32

Author(s):

K. P. Rakesh ◽

Shi-Meng Wang ◽

Jing Leng ◽

L. Ravindar ◽

Abdullah M. Asiri ◽

...

Keyword(s):

Drug Resistance ◽

Anticancer Agents ◽

Side Effect ◽

Docking Studies ◽

Multi Drug Resistance ◽

Anticancer Activities ◽

Pharmacological Activities ◽

Synthetic Compounds ◽

Structure Activity ◽

Anticancer Drug Discovery

Cancer is the second leading cause of death worldwide. There is always a huge demand for novel anticancer drugs and diverse new natural or synthetic compounds are developed continuously by scientists. Presently, a large number of drugs in clinical practice have showed pervasive side effect and multidrug resistance. Sulfonyl or sulfonamide hybrids became one of the most attractive subjects due to their broad spectrum of pharmacological activities. Sulfonyl hybrids were broadly explored for their anticancer activities and it was found that they possess minimum side effect along with multi-drug resistance activity. This review describes the most recent applications of sulfonyl hybrid analogues in anticancer drug discovery and further discusses the mechanistic insights, structure-activity relationships and molecular docking studies for the potent derivatives.

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Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200627212128 ◽

2020 ◽

Vol 20 (14) ◽

pp. 1714-1721

Author(s):

Hatem A. Abuelizz ◽

El Hassane Anouar ◽

Mohamed Marzouk ◽

Mizaton H. Hasan ◽

Siti R. Saleh ◽

...

Keyword(s):

Molecular Docking ◽

Kojic Acid ◽

Docking Studies ◽

Breast Adenocarcinoma ◽

Amino Acid Residues ◽

New Class ◽

Structure Activity ◽

Tyrosinase Inhibitors ◽

Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

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