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Future Medicinal Chemistry

Kristy A Carpenter, David S Cohen, Juliet T Jarrell, Xudong Huang
Current drug development is still costly and slow given tremendous technological advancements in drug discovery and medicinal chemistry. Using machine learning (ML) to virtually screen compound libraries promises to fix this for generating drug leads more efficiently and accurately. Herein, we explain the broad basics and integration of both virtual screening (VS) and ML. We then discuss artificial neural networks (ANNs) and their usage for VS. The ANN is emerging as the dominant classifier for ML in general, and has proven its utility for both structure-based and ligand-based VS...
October 5, 2018: Future Medicinal Chemistry
Hui-Yan Wang, Ying Shen, Hao Zhang, Yuan-Yuan Hei, Hong-Yi Zhao, Minhang Xin, She-Min Lu, San-Qi Zhang
AIM: The discovery and development of novel agents simultaneously targeting PI3K/AKT/mammalian target of rapamycin and Ras/RAF/MEK, two signaling pathways, are urgent to improve the curative effect of kinase inhibitors and overcome acquired resistance. METHODS/RESULTS: In the present study, 2-(2-aminopyrimidin-5-yl)-4-(morpholin-4-yl)-6-(N-cyclopropyl-N- (1-benzoylpiperidin-4-yl))triazines/pyrimidines were designed as PI3K and BRAF dual inhibitors. The synthesized 20 compounds exhibited potent antiproliferative effects in vitro against HCT116, A375, MCF-7, Colo205, A549 and LOVO cancer cell lines...
October 2018: Future Medicinal Chemistry
Magdalena Perużyńska, Katarzyna Piotrowska, Marta Tkacz, Mateusz Kurzawski, Łukasz Struk, Aleksandra Borzyszkowska, Tomasz J Idzik, Jacek G Sośnicki, Marek Droździk
AIM: The mitotic spindle plays a key role in cell division which makes it an important target in cancer therapy. In the present study the antiproliferative activity of 4-benzyl-5-phenyl-3,4-dihydropyrimidine-2(1H)-thione (1) and its pyridine bioisoster (2) were evaluated and compared with monastrol (MON), the first known cell-permeable small molecule which disrupts bipolar spindle formation by inhibiting Eg5-kinesin activity. RESULTS: Our data revealed that compound 2 showed higher antiproliferative activity than MON against MCF7 and A375 cell lines and comparable reversible cell cycle inhibition in G2/M phase...
October 2018: Future Medicinal Chemistry
Vassilios Myrianthopoulos
No abstract text is available yet for this article.
October 2018: Future Medicinal Chemistry
Ciro Mercurio, Mario Varasi
No abstract text is available yet for this article.
October 2018: Future Medicinal Chemistry
Nestor Prieto-Dominguez, Austin Y Shull, Yong Teng
FGF19 is a noncanonical FGF ligand that can control a broad spectrum of physiological responses, which include bile acid homeostasis, liver metabolism and glucose uptake. Many of these responses are mediated by FGF19 binding to its FGFR4/β-klotho receptor complex and controlling activation of an array of intracellular signaling events. Overactivation of the FGF19/FGFR4 axis has been implicated in tumorigenic formation, progression and metastasis, and inhibitors of this axis have recently been developed for single agent use or in combination with other anticancer drugs...
October 2018: Future Medicinal Chemistry
Felix Torres, Julien Orts
No abstract text is available yet for this article.
October 2018: Future Medicinal Chemistry
Priyanka Chandel, Ravindra K Rawal, Rupinder Kaur
From ancient times, natural products have been continuously used as therapeutic agents in the treatment of various ailments. Many drugs from the natural origin are available in the market as potent medicines. Over expression of cyclooxygenase-2 (COX-2) enzyme is associated with various physical disorders like various types of inflammations associated with cardiovascular diseases or malignancies. The COX-2 inhibitory activity of many active constituents derived from plants is well established in the literature...
October 2018: Future Medicinal Chemistry
Maria E Mavrogeni, Filippos Pronios, Danae Zareifi, Sofia Vasilakaki, Olivier Lozach, Leonidas Alexopoulos, Laurent Meijer, Vassilios Myrianthopoulos, Emmanuel Mikros
BACKGROUND: Virtual screening is vital for contemporary drug discovery but striking performance fluctuations are commonly encountered, thus hampering error-free use. Results and Methodology: A conceptual framework is suggested for combining screening algorithms characterized by orthogonality (docking-scoring calculations, 3D shape similarity, 2D fingerprint similarity) into a simple, efficient and expansible python-based consensus ranking scheme. An original experimental dataset is created for comparing individual screening methods versus the novel approach...
October 2018: Future Medicinal Chemistry
Hemlata M Mali, Sandip S Sabale, Mariam S Degani, Rachana Borkute, Amit S Choudhari, Dhiman Sarkar, Vagolu Siva Krishna, Dharmarajan Sriram
AIM: A series of coumarin derivatives was designed as potential antituberculosis agents. RESULTS: The compounds were screened against active and dormant Mycobacterium tuberculosis (Mtb). Compounds 3k and 3n were found to have the most promising activity against replicating MtbH37Rv exhibiting minimum inhibitory concentration of 4.63 and 9.75 μM respectively. The compounds were also effective against dormant MtbH37Rv exhibiting more potency than the standard drugs, isoniazid and rifampicin...
October 2018: Future Medicinal Chemistry
Marjan Aghvami, Ahmad Salimi, Peyman Eshghi, Mohammad H Zarei, Shabnam Farzaneh, Fatemeh Sattari, Afshin Zarghi, Jalal Pourahmad
AIM: Acute lymphoblastic leukemia (ALL) is known as a barely curable malignancy. Particular mutations involved in apoptosis may have a main role in the onset of ALL in the pediatric patients. It has been proven that cycloxygenase-2 is capable of impairing the apoptosis pathway through mitochondria in tumor cells. METHODOLOGY: In this study, we investigated selective toxicity of a newly synthesized chalconeferrocenyl derivative as a selective cycloxygenase-2 inhibitor in ALL and healthy B-lymphocytes, and also isolated mitochondria obtained from them...
October 1, 2018: Future Medicinal Chemistry
Aleksandra Kładna, Paweł Berczyński, Oya Bozdağ Dündar, Meltem Ceylan Ünlüsoy, Elmas Sarı, Bernadetta Bakinowska, Irena Kruk, Hassan Y Aboul-Enein
AIM: Synthesis of novel 2(2-hydroxyphenyl) pyrimidine/benzothiazole piperazinyl-substituted flavones end evaluate their antioxidant activity. RESULTS: Six novel 2-(2-hydroxyphenyl) pyrimidine/benzothiazole-substituted flavones were synthesized, their structures were confirmed by elementary and spectral analyses. The compounds were evaluated for their in vitro antioxidant potency by employing various antioxidant assays. CONCLUSION: All tested compounds acted as scavengers of free radicals like hydroxyl (15-45%), 2,2-diphenyl-1-picrylhydrazyl• (17-48%) at 1...
October 2018: Future Medicinal Chemistry
Yanhui Zhang, Yongli Du
Protein tyrosine phosphatase1B (PTP1B), a significant negative regulator in insulin and leptin signaling pathways, has emerged as a promising drug target for Type II diabetes mellitus and obesity. Numerous potent PTP1B inhibitors have been discovered within both academia and pharmaceutical industry. However, nearly all medicinal chemistry efforts have been severely hindered because a vast majority of them demonstrate poor membrane permeability and low-selectivity, especially over T-cell protein tyrosine phosphatase (TCPTP)...
October 2018: Future Medicinal Chemistry
Shama Khan, Imane Bjij, Fisayo A Olotu, Clement Agoni, Emmanuel Adeniji, Mahmoud E S Soliman
AIM: Irreversible covalent inhibition of biological targets in disease pathogenesis is an emerging field in drug design. Computational techniques have assumed a critical role in understanding covalent enzyme inhibition. However, a gap currently exists with regards to the reliability and reproducibility of currently available protocols available in literature and open scientific forums. METHODOLOGY/RESULTS: Appropriate ligand and protein target are selected, docked covalently or noncovalently using respective docking tools...
October 2018: Future Medicinal Chemistry
Bartosz Skalski, Bogdan Kontek, Beata Olas, Jerzy Żuchowski, Anna Stochmal
AIM: The main objective of our studies was to determine the chemical composition and biological activities (antioxidant and anticoagulant properties) of two standardized phenolic fractions from sea buckthorn twig and leaf, and two standardized nonpolar fractions from twig and leaf in human plasma in vitro. MATERIAL & METHODS:  Appropriately prepared extracts from sea buckthorn twigs and leaves were used. Markers of oxidative stress and hemostasis were determined in this work...
October 2018: Future Medicinal Chemistry
Peter V Dubovskii, Anastasia A Ignatova, Pavel E Volynsky, Igor A Ivanov, Maxim N Zhmak, Alexey V Feofanov, Roman G Efremov
AIM: Spider venom is a rich source of antibacterial peptides, whose hemolytic activity is often excessive. METHODOLOGY: How to get rid of it? Using latarcins from Lachesana tarabaevi and oxyopinin Oxt 4a from Oxyopes takobius spider venoms we performed coarse-grained molecular dynamics simulations of these peptides in the presence of lipid bilayers, mimicking erythrocyte membranes. This identified hemolytically active fragments within Oxt 4a and latarcins. Then, we synthesized five 20-residue peptides, containing different parts of the Oxt 4a and latarcin-1 sequence, carrying mutations within the identified regions...
October 1, 2018: Future Medicinal Chemistry
Anja Kolarič, Nikola Minovski
No abstract text is available yet for this article.
October 1, 2018: Future Medicinal Chemistry
Nikhil Shri Sahajpal, Alka Chaubey, Rajesh Kumar Goel, Subheet Kumar Jain
No abstract text is available yet for this article.
October 1, 2018: Future Medicinal Chemistry
Livia Neves Borgheti-Cardoso, Xavier Fernàndez-Busquets
No abstract text is available yet for this article.
October 1, 2018: Future Medicinal Chemistry
Adnan A Bekhit, Manal N Saudi, Ahmed Mm Hassan, Salwa M Fahmy, Tamer M Ibrahim, Doaa Ghareeb, Aya M El-Seidy, Sayed M Al-Qallaf, Huda J Habib, Alaa El-Din A Bekhit
AIM: Novel open chain and cyclized derivatives containing pyrazole scaffold were designed, synthesized and evaluated as antileishmanial compounds. Methodology & results: In silico reverse docking experiment suggested Leishmania major pteridine reductase (Lm-PTR1) as a putative target for the synthesized compounds. In vitro antileishmanial screening against L. major promastigotes and amastigotes using miltefosine and amphotericin B as references showed that the majority of the compounds displayed activity higher than miltefosine...
October 1, 2018: Future Medicinal Chemistry
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