scholarly journals Studies on the Dual Activity of EGFR and HER-2 Inhibitors Using Structure-Based Drug Design Techniques

2018 ◽  
Vol 19 (12) ◽  
pp. 3728 ◽  
Author(s):  
Rafaela de Angelo ◽  
Michell Almeida ◽  
Heberth de Paula ◽  
Kathia Honorio
Keyword(s):  
Similarity Index ◽  
Chemical Properties ◽  
Drug Candidate ◽  
Dual Inhibitor ◽  
Structure Based Drug Design ◽  
Biological Targets ◽  
Drug Candidates ◽  
Molecular Interaction Fields ◽  
Her 2 ◽  
New Compounds

HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r2 calibration = 0.98 and q2cv = 0.83) and EGFR (r2 calibration = 0.98 and q2cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r2 calibration = 0.92 and q2cv = 0.74) and EGFR (r2 calibration = 0.97 and q2cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer.

scholarly journals Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

2020 ◽  
Vol 18 (5) ◽  
pp. 348-407 ◽  
Author(s):  
Vanessa Silva Gontijo ◽  
Flávia P. Dias Viegas ◽  
Cindy Juliet Cristancho Ortiz ◽  
Matheus de Freitas Silva ◽  
Caio Miranda Damasio ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Rational Design ◽  
Brain Regions ◽  
Molecular Hybridization ◽  
Drug Candidate ◽  
New Paradigm ◽  
New Approach ◽  
Biological Targets ◽  
Drug Candidates ◽  
Biochemical Pathways

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer’s Disease: An Update

2018 ◽  
Vol 25 (29) ◽  
pp. 3491-3525 ◽  
Author(s):  
Matheus de Freitas Silva ◽  
Kris Simone Tranches Dias ◽  
Vanessa Silva Gontijo ◽  
Cindy Juliet Cristancho Ortiz ◽  
Claudio Viegas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Neurodegenerative Disorder ◽  
Drug Candidate ◽  
Modern Approach ◽  
Biological Targets ◽  
Drug Candidates ◽  
Multiple Factors ◽  
Recent Approach

Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics

2018 ◽  
Vol 25 (5) ◽  
pp. 636-658 ◽  
Author(s):  
Jan Pokorny ◽  
Lucie Borkova ◽  
Milan Urban
Keyword(s):  
Biological Activities ◽  
Synthetic Approach ◽  
Clinical Use ◽  
New Approach ◽  
Click Reactions ◽  
Drug Candidates ◽  
The Past ◽  
Low Toxicity ◽  
New Compounds ◽  
Potential Therapeutics

Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

Synthesis of Pyrazolofuropyrazine via One-Pot SNAr Reaction and Intramolecular Direct C–H Arylation

Synthesis ◽  
2018 ◽  
Vol 50 (07) ◽  
pp. 1493-1498 ◽  
Author(s):  
Shinichiro Fuse ◽  
Hiroyuki Nakamura ◽  
Megumi Inaba ◽  
Shinichi Sato ◽  
Manjusha Joshi
Keyword(s):  
Drug Discovery ◽  
Rapid Development ◽  
Ring System ◽  
Biologically Active ◽  
Drug Candidate ◽  
One Pot ◽  
Ring Systems ◽  
Drug Candidates ◽  
Fused Ring ◽  
Snar Reaction

Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot SNAr reaction/intramolecular C–H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.

scholarly journals Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Jérémie Piton ◽  
Anthony Vocat ◽  
Andréanne Lupien ◽  
Caroline S. Foo ◽  
Olga Riabova ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Antitubercular Activity ◽  
Cysteine Residue ◽  
Drug Candidate ◽  
Structure Based Drug Design ◽  
Content Type ◽  
Active Site Cysteine ◽  
Covalent Adducts

ABSTRACT Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

scholarly journals A Study of Zooplankton Community in Dukan Lake, Kurdistan Region-Iraq, with a New Record of Craspedacusta sowerbii Lankester (1880) Medusa (Cnidaria: Hydrozoa)

2017 ◽  
Vol 14 (4) ◽  
pp. 735-741 ◽  
Author(s):  
Baghdad Science Journal
Keyword(s):  
Similarity Index ◽  
Chemical Properties ◽  
Zooplankton Community ◽  
Ion Concentration ◽  
Hydrogen Ion Concentration ◽  
Alkaline Side ◽  
Physical And Chemical ◽  
First Time ◽  
Jaccard's Similarity Index ◽  
And Chemical Properties

A study of Zooplankton community has been carried out at four selected sites on Dukan Lake. Samples of water and zooplankton were collected monthly for the period from July 2015 to February 2016. Some physical and chemical properties of water were studied and the results showed that the air temperature were ranged from 0 to 36.16 °C, water temperature ranged from 2.83 to 34.66 °C, hydrogen ion concentration of studied sites were found to lie in alkaline side, it was ranged between 6.87 to 8.57, electrical conductivity ranged from 190.79 to 850.08 µs.cm­¹, turbidity ranged from 0.9-7.7 NTU, and dissolved oxygen from 3.3 to 6.8 mg.l-¹ while BOD5 were ranged from 0.53 to 34.66 mg.l-¹. Concerning to the zooplankton, 37 species were identified which belonged to Cladocera (48.38%), Copepod (43.28%), Rotifera (8.23%), Targigrada (0.08%) and Cnidaria (0.1%). The medusa of Craspedacusta sowerbii Lankester (1880) was recorded for the first time in Iraq. Regarding to zooplankton community, rotifer were ranged between 0 to 690.91 ind.m-3, Copepoda from 54.55 to 5927.27 ind.m-3 and Cladocera ranged from 18.18 to 6072.73 ind.m-3. According to Shanon-Weiner index, species diversity for zooplankton invertebrates was ranged from 0.325 to 1.091 bits/ind. Jaccard’s similarity index showed that the highest similarity was recorded between site (1) and site (4) with 40.74%.

scholarly journals Structure-based screening of drug candidates targeting the SARS-CoV-2 envelope protein

2021 ◽  
Author(s):  
Xin Xia ◽  
Yuwei Zhang ◽  
Songling Li ◽  
Hengwei Lin ◽  
Zhiqiang Yan
Keyword(s):  
Structural Model ◽  
Hematologic Malignancies ◽  
Drug Candidate ◽  
Functional Assay ◽  
Protein Inhibitor ◽  
Patch Clamp Recording ◽  
Drug Candidates ◽  
E Protein ◽  
Future Drug ◽  
Protein Amino Acids

The COVID-19 (coronavirus disease 2019) pandemic is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 produces a small hydrophobic envelope (E) protein which shares high homology with SARS-CoV E protein. By patch-clamp recording, the E protein is demonstrated to be a cation-selective ion channel. Furthermore, the SARS-CoV-2 E protein can be blocked by a SARS-CoV E protein inhibitor hexamethylene amiloride. Using structural model and virtual screening, another E protein inhibitor AZD5153 is discovered. AZD5153 is a bromodomain protein 4 inhibitor against hematologic malignancies in clinical trial. The E protein amino acids Phe23 and Val29 are key determinants for AZD5153 sensitivity. This study provides two promising lead compounds and a functional assay of SARS-CoV-2 E protein for the future drug candidate discovery.

scholarly journals Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736

2020 ◽  
Vol 4 (7) ◽  
pp. 1478-1491 ◽  
Author(s):  
Andrew S. Moore ◽  
Amir Faisal ◽  
Grace W. Y. Mak ◽  
Farideh Miraki-Moud ◽  
Vassilios Bavetsias ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Human Tumor ◽  
Drug Candidate ◽  
Tyrosine Kinase Domain ◽  
Human Tumor Xenograft ◽  
Dual Inhibitor ◽  
Aurora Kinases ◽  
Acute Myeloid

Abstract Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.

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