3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamides as a New Class of Synthetic Histone Deacetylase Inhibitors. 3. Discovery of Novel Lead Compounds through Structure-Based Drug Design and Docking Studies†,Δ

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of β-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.

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STRUCTURAL EXPLORATION AND PHARMACOPHORIC INVESTIGATION OF PYRAZOLE BASED ANALOGS AS NOVEL HISTONE DEACETYLASE 1 INHIBITOR USING COMBINATORIAL STUDIES

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2018v10i3.22735 ◽

2018 ◽

Vol 10 (3) ◽

pp. 90

Author(s):

Avineesh Singh ◽

Harish Rajak

Keyword(s):

Molecular Docking ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Research Work ◽

3D Qsar ◽

Qsar Model ◽

Docking Studies ◽

Inhibition Activity ◽

Design Strategies ◽

Histone Deacetylase 1

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

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Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya

Biofarmasi Journal of Natural Product Biochemistry ◽

10.13057/biofar/f160102 ◽

2018 ◽

Vol 16 (1) ◽

pp. 8-21

Author(s):

MANYIM SCOLASTICA ◽

ALBERT J. NDAKALA ◽

SOLOMON DERESE

Keyword(s):

Natural Products ◽

Drug Design ◽

Active Site ◽

Docking Studies ◽

Moderate Activity ◽

Vigorous Activity ◽

Structure Based Drug Design ◽

Web Based ◽

Ic50 Values ◽

Accessible Form

Scolastica M, Ndakala AJ, Derese S. 2018. Modeling and synthesis of antiplasmodial chromones, chromanones and chalcones based on natural products of Kenya. Biofarmasi J Nat Prod Biochem 16: 8-21. Despite numerous research that has been done on plants of Kenya resulting in the isolation of thousands of natural products, data on these natural products are not systematically organized in a readily accessible form. This has urged the construction of a web-based database of natural products of Kenya. The database is named Mitishamba and is hosted at http://mitishamba.uonbi.ac.ke. The Mitishamba database was queried for chromones, chromanones, and chalcones that were subjected to structure-based drug design using Fred (OpenEye) docking utility program with 1TV5 PDB structure of the PfDHODH receptor to identify complex of ligands that bind with the active site. Ligand-based drug design (Shape and electrostatics comparison) was also done on the ligands against query A77 1726 (38) (the ligand that co-crystallized with PfDHODH receptor) using ROCS and EON programs, respectively, of OpenEye suite. There was a substantial similarity among the top performing ligands in the docking studies with shape and electrostatic comparison that led to the identification of compounds of interest which were targeted for synthesis and antiplasmodial assay. In this study, a chromanone (7-hydroxy-2-(4-methoxyphenyl) chroman-4-one (48)) and two intermediate chalcones (2',4'-dihydroxy-4-methoxychalcone (45) and 2’,4’-dihydroxy-4-chlorochalcone (47)), were synthesized and subjected to antiplasmodial assay. Among these substances, 45 showed vigorous activity, whereas 47 and 48 had moderate activity against the chloroquine resistant K1 strain of P. falciparum with IC50 values of 4.56±1.66, 17.62 ± 5.94 and 18.01 ±1.66 µg/ml, respectively. Since the synthesized compounds showed antiplasmodial potential, there is a need for further computational refinement of these compounds to optimize their antiplasmodial activity.

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Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

Methods and Algorithms for Molecular Docking-Based Drug Design and Discovery - Advances in Medical Technologies and Clinical Practice ◽

10.4018/978-1-5225-0115-2.ch008 ◽

2016 ◽

pp. 196-219

Author(s):

Sanchaita Rajkhowa ◽

Ramesh C. Deka

Keyword(s):

Molecular Docking ◽

Drug Discovery ◽

Drug Design ◽

High Throughput Screening ◽

Docking Studies ◽

Stable Complex ◽

Scoring Functions ◽

Binding Modes ◽

Structure Based Drug Design ◽

Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

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Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors

Bioorganic Chemistry ◽

10.1016/j.bioorg.2017.03.005 ◽

2017 ◽

Vol 72 ◽

pp. 32-41 ◽

Cited By ~ 19

Author(s):

Mamdouh F.A. Mohamed ◽

Montaser Sh.A. Shaykoon ◽

Mostafa H. Abdelrahman ◽

Bakheet E.M. Elsadek ◽

Ahmed S. Aboraia ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Docking Studies ◽

Biological Evaluation ◽

Design Synthesis ◽

Chalcone Derivatives

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Design, synthesis and docking studies on benzamide derivatives as histone deacetylase inhibitors

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.06.001 ◽

2011 ◽

Vol 21 (16) ◽

pp. 4924-4927 ◽

Cited By ~ 11

Author(s):

Aijun Lu ◽

Hongpeng Luo ◽

Minfeng Shi ◽

Gang Wu ◽

Yunxia Yuan ◽

...

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Docking Studies ◽

Design Synthesis ◽

Benzamide Derivatives

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Regulation of Immune Responses by Histone Deacetylase Inhibitors

ISRN Hematology ◽

10.5402/2012/690901 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

Paul V. Licciardi ◽

Tom C. Karagiannis

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

Adaptive Immune Response ◽

Immune Gene ◽

Epigenetic Factors ◽

New Class ◽

Adaptive Immune ◽

Immune Gene Expression

Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed.

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PHARMACOPHORIC SCREENING OF VARIOUS ENDOPHYTIC FUNGAL METABOLITES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i5.17157 ◽

2017 ◽

Vol 10 (5) ◽

pp. 140

Author(s):

Brindha Devi ◽

Rajagopala K ◽

Esther Elizabeth

Keyword(s):

Drug Design ◽

Pharmacophore Model ◽

Antioxidant Property ◽

Docking Studies ◽

Fungal Metabolites ◽

Kcal Mole ◽

Structure Based Drug Design ◽

Docking Score ◽

Drug Candidates ◽

Anti Inflammatory

Objective: To screen various endophytic fungal metabolites toward anti-inflammatory, anticancer, and antioxidant property virtually.Methods: In this study, 14 bioactive compounds reported from endophytic fungi have taken for structure-based drug design. With the help of softwareSchrodinger, different modules were used to perform screening of top active compounds. Ligprep, epharm, Glide, Quikprop are the modules were used from the software for our study. Identification of leads, pharmacophore model generation, and molecular docking studies were assessed using this software.Results: After the screening of molecules virtually, the most bioactive anti-inflammatory compound was found to be cycloepoxytriol with the dockingscore of −7.511 kcal/mole, and the most active anticancer compound was found to be Phomol with the docking score of −9.778 kcal/mole. The mostactive antioxidant compound was found to be Phomol with the docking score of −9.970 kcal/mole. Further account the potential of the compoundsto act as efficient drug candidates, their absorption, distribution, metabolism, and excretion properties were also predicted. All the compounds wereshown to correlate well with all properties virtually.Conclusion: In conclusion, using structure-based drug design, we have obtained some promising leads for anti-inflammatory, anticancer, andantioxidant drug discovery. The discovery of compounds from natural products is very potent for formulating new drugs.Keywords: Endophytes, Anti-inflammatory, Anticancer, Antioxidant, Absorption; distribution; metabolism and excretion.

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