1,985 results match your criteria drug-like properties

Identification of novel potential inhibitors of varicella-zoster virus thymidine kinase from ethnopharmacologic relevant plants through an approach.

J Biomol Struct Dyn 2021 Sep 17:1-16. Epub 2021 Sep 17.

Department of Biochemistry, School of Biological Sciences, University of Cape Coast, Cape Coast, Ghana.

Although Varicella or chickenpox infection which is caused by the varicella-zoster virus (VZV) has significantly been managed through vaccination, it remains an infection that poses threats to the nearest future due to therapeutic drawbacks. The focus of this research was geared towards screening for the identification of novel compounds in plants of ethnopharmacological relevance in the treatment of chicken pox in West Africa. The work evaluated 65 compounds reported to be present in and to identify potential inhibitors of thymidine kinase, the primary drug target of varicella zoster virus. Read More

View Article and Full-Text PDF
September 2021

Pharmacological Properties of 2,4,6-Trihydroxy-3-Geranyl Acetophenone and the Underlying Signaling Pathways: Progress and Prospects.

Front Pharmacol 2021 31;12:736339. Epub 2021 Aug 31.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a bioactive phloroglucinol compound found in (Champ. ex Benth.) T. Read More

View Article and Full-Text PDF

Chromones: Privileged scaffold in anticancer drug discovery.

Chem Biol Drug Des 2021 Sep 13. Epub 2021 Sep 13.

Department of Chemistry, Vidya Bharati College, Amravati, Maharashtra, India.

In the design and discovery of anticancer drugs, various natural heterocyclic scaffolds have attracted considerable interest as privileged structures. For rational drug design, some of the natural scaffolds such as chromones have exhibited wide acceptability due to their drug-like properties. Among the approved anticancer drugs, the scaffolds with high selectivity for a small group of closely related targets are of importance. Read More

View Article and Full-Text PDF
September 2021

New Chalcone Derivatives as Effective Anti-SARS-CoV-2 Agents.

Int J Clin Pract 2021 Sep 14:e14846. Epub 2021 Sep 14.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mersin University, Mersin, 33169, Turkey.

Aims: Flavonoids and related compounds, such as quercetin-based antiviral drug Gene-Eden-VIR/Novirin, inhibit the protease of severe acute respiratory syndrome coronavirus (SARS-CoV-2). The alkylated chalcones isolated from Angelica keiskei inhibit SARS-CoV proteases. In this study, we aimed to compare the anti-SARS CoV-2 activities of both newly synthesized chalcone derivatives and these two drugs. Read More

View Article and Full-Text PDF
September 2021

New indolesulfonamide derivatives targeting the colchicine site of tubulin: synthesis, anti-tumour activity, structure-activity relationships, and molecular modelling.

J Enzyme Inhib Med Chem 2021 Dec;36(1):2025-2044

Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Salamanca, Spain.

Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Read More

View Article and Full-Text PDF
December 2021

Engineered Multivalent Nanobodies Potently and Broadly Neutralize SARS-CoV-2 Variants.

Adv Ther (Weinh) 2021 Aug 2;4(8):2100099. Epub 2021 Aug 2.

Department of Chemical Engineering University of Michigan Ann Arbor MI 48109 USA.

The COVID-19 pandemic continues to be a severe threat to human health, especially due to current and emerging SARS-CoV-2 variants with potential to escape humoral immunity developed after vaccination or infection. The development of broadly neutralizing antibodies that engage evolutionarily conserved epitopes on coronavirus spike proteins represents a promising strategy to improve therapy and prophylaxis against SARS-CoV-2 and variants thereof. Herein, a facile multivalent engineering approach is employed to achieve large synergistic improvements in the neutralizing activity of a SARS-CoV-2 cross-reactive nanobody (VHH-72) initially generated against SARS-CoV. Read More

View Article and Full-Text PDF

Docking and mutagenesis studies lead to improved inhibitor development of ML355 for human platelet 12-lipoxygenase.

Bioorg Med Chem 2021 Aug 4;46:116347. Epub 2021 Aug 4.

Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, United States. Electronic address:

Human platelet 12-(S)-Lipoxygenase (12-LOX) is a fatty acid metabolizing oxygenase that plays an important role in platelet activation and cardiometabolic disease. ML355 is a specific 12-LOX inhibitor that has been shown to decrease thrombosis without prolonging hemostasis and protect human pancreatic islets from inflammatory injury. It has an amenable drug-like scaffold with nM potency and encouraging ADME and PK profiles, but its binding mode to the active site of 12-LOX remains unclear. Read More

View Article and Full-Text PDF

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies.

J Med Chem 2021 Sep 9. Epub 2021 Sep 9.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as , , , , , and , were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. Read More

View Article and Full-Text PDF
September 2021

Design, synthesis and evaluation of novel β-carboline ester analogues as potential anti-leishmanial agents.

J Biomol Struct Dyn 2021 Sep 6:1-16. Epub 2021 Sep 6.

Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani, Rajasthan, India.

Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of β-carboline ester derivatives against leishmaniasis. Read More

View Article and Full-Text PDF
September 2021

Development of an Antibiotic Resistance Breaker to Resensitize Drug-Resistant : and Approach.

Front Cell Infect Microbiol 2021 16;11:700198. Epub 2021 Aug 16.

Quorum Sensing Laboratory, Centre of Research in Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India.

Efflux pumps are one of the predominant microbial resistant mechanisms leading to the development of multidrug resistance. In , overexpression of NorA protein enables the efflux of antibiotics belonging to the class of fluoroquinolones and, thus, makes resistant. Hence, NorA efflux pumps are being extensively exploited as the potential drug target to evade bacterial resistance and resensitize bacteria to the existing antibiotics. Read More

View Article and Full-Text PDF

Discovery of novel hit compounds as potential HDAC1 inhibitors: The case of ligand- and structure-based virtual screening.

Comput Biol Med 2021 Aug 26;137:104808. Epub 2021 Aug 26.

Department of Pharmacy, University of Pisa, Via Bonanno 6, I-56126 Pisa, Italy. Electronic address:

Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. Read More

View Article and Full-Text PDF

Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors.

Comput Struct Biotechnol J 2021 9;19:4486-4496. Epub 2021 Aug 9.

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok körútja 2, Budapest 1117, Hungary.

The ubiquitin-proteasome system is responsible for the degradation of proteins and plays a critical role in key cellular processes. While the constitutive proteasome (cPS) is expressed in all eukaryotic cells, the immunoproteasome (iPS) is primarily induced during disease processes, and its inhibition is beneficial in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Oxathiazolones were reported to selectively inhibit iPS over cPS, and the inhibitory activity of several oxathiazolones against iPS was experimentally determined. Read More

View Article and Full-Text PDF

[Network pharmacology study of Tibetan medicine Corydalis Herba against acute myocardial ischemia].

Zhongguo Zhong Yao Za Zhi 2021 Jun;46(12):3058-3065

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine Beijing 100029, China.

In this study, the compound search was completed through SciFinder and CNKI databases, and the drug-like properties were screened in FAFdrugs4 and SEA Search Server databases. In addition, based on the target sets related to acute myocardial ischemia(AMI) searched in disease target databases such as OMIM database, GeneCards database and DrugBank, a network diagram of chemical component-target-pathway-disease was established via Cytoscape to predict the potential active components of Corydalis Herba, a traditional Tibetan herbal medicine which derived from the aerial parts of Corydalis hendersonii and C. mucronifera against AMI. Read More

View Article and Full-Text PDF

Discovery of potential inhibitors for stat3: ligand based 3D pharmacophore, virtual screening, molecular docking, dynamic studies and evaluation.

J Biomol Struct Dyn 2021 Aug 31:1-19. Epub 2021 Aug 31.

Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamil Nadu, India.

A large analysis of the signal transducer and activator of transcription (STAT3) in cancer is currently being carried out. It regulates gene expression, which is required for normal cellular functions such as differentiation, cell growth, proliferation, survival, maturation, and immunity. A ligand-based pharmacophore model was created using 3 D QSAR pharmacophore generation methodology in Discovery studio 4. Read More

View Article and Full-Text PDF

Screening of anti- phytochemicals, based on the potential inhibitory effect on OmpA and OmpW functions.

R Soc Open Sci 2021 Aug 18;8(8):201652. Epub 2021 Aug 18.

Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), PO Box 14155-6343, Tehran, Iran.

Therapeutic options including last-line or combined antibiotic therapies for multi-drug-resistant strains of are ineffective. The outer membrane protein A (OmpA) and outer membrane protein W (OmpW) are two porins known for their different cellular functions. Identification of natural compounds with the potentials to block these putative porins can attenuate the growth of the bacteria and control the relating diseases. Read More

View Article and Full-Text PDF

In-silico screening and identification of phytochemicals from as potential inhibitors of sodium-glucose co-transporter 2 for treating diabetes.

J Biomol Struct Dyn 2021 Aug 28:1-18. Epub 2021 Aug 28.

Department of Chemical Engineering, University of the Philippines Diliman, Quezon City, Philippines.

Sodium-glucose co-transporter 2 (SGLT-2) is a major transport protein responsible for reabsorption of glucose from the kidney back to the bloodstream. Inhibiting this protein effectively lowers the glucose level of diabetic patients; however, the use of synthetic SGLT-2 inhibitors has been linked to some serious adverse effects. There is a need to identify safer alternatives that are equally or more effective as the current inhibitor drugs. Read More

View Article and Full-Text PDF

Protein-Small Molecule Interactions in Native Mass Spectrometry.

Chem Rev 2021 Aug 27. Epub 2021 Aug 27.

School of Chemistry, University of New South Wales, Sydney, New South Wales 2052, Australia.

Small molecule drug discovery has been propelled by the continual development of novel scientific methodologies to occasion therapeutic advances. Although established biophysical methods can be used to obtain information regarding the molecular mechanisms underlying drug action, these approaches are often inefficient, low throughput, and ineffective in the analysis of heterogeneous systems including dynamic oligomeric assemblies and proteins that have undergone extensive post-translational modification. Native mass spectrometry can be used to probe protein-small molecule interactions with unprecedented speed and sensitivity, providing unique insights into polydisperse biomolecular systems that are commonly encountered during the drug discovery process. Read More

View Article and Full-Text PDF

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways.

Int J Mol Sci 2021 Aug 23;22(16). Epub 2021 Aug 23.

Computational and Chemical Biology, Italian Institute of Technology, 16163 Genoa, Italy.

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. Read More

View Article and Full-Text PDF

Discovery of Novel Dihydrothiopyrano[4,3-]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles.

J Med Chem 2021 Aug 25. Epub 2021 Aug 25.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan, Shandong 250012, PR China.

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3-]pyrimidine derivatives were rationally designed scaffold hopping and molecular hybridization strategies. Notably, compound yielded exceptionally potent antiviral activities (EC = 4.44-54. Read More

View Article and Full-Text PDF

Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis.

Antimicrob Agents Chemother 2021 Aug 23:AAC0174420. Epub 2021 Aug 23.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous and assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of infection and in healthy animals. Read More

View Article and Full-Text PDF

The rise and rise of protein degradation: Opportunities and challenges ahead.

Drug Discov Today 2021 Aug 20. Epub 2021 Aug 20.

Amphista Therapeutics Ltd, BioCity, Bo'Ness Rd, Newhouse, Motherwell ML1 5UH, UK. Electronic address:

The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to the clinic. Despite this remarkable progress, there remain many opportunities to improve current, first-generation approaches even further. Our expanding knowledge will allow discovery of new degrading mechanisms with potential to address several limitations of current approaches, including improving scope and efficiency of degradation, improving drug-like properties of degraders, and reducing potential for the emergence of acquired resistance. Read More

View Article and Full-Text PDF

Structural optimization, synthesis and in vitro synergistic anticancer activities of combinations of new N3-substituted dihydropyrimidine calcium channel blockers with cisplatin and etoposide.

Bioorg Chem 2021 Aug 11;115:105262. Epub 2021 Aug 11.

Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Sciences, South Dakota State University, Brookings, SD 57006, USA. Electronic address:

T-type calcium channels are considered potential drug targets to combat cancer. Combining T-type calcium channel blockers with conventional chemotherapy drugs represents a promising strategy towards successful cancer treatment. From this perspective, we report in this study the design and synthesis of a novel series of N3-sustituted dihydropyrimidines (DHPMs) as anticancer adjuvants to cisplatin (Cis) and etoposide (Eto). Read More

View Article and Full-Text PDF

A network pharmacology analysis on drug-like compounds from Ganoderma lucidum for alleviation of atherosclerosis.

J Food Biochem 2021 Sep 18;45(9):e13906. Epub 2021 Aug 18.

Department of Bio-Health Convergence, College of Biomedical Science, Kangwon National University, Chuncheon, Korea.

Ganoderma lucidum (GL) is known as a potent alleviator against chronic inflammatory disease like atherosclerosis (AS), but its mechanisms against AS have not been unveiled. This research aimed to identify the key compounds(s) and mechanism(s) of GL against AS through network pharmacology. The compounds from GL were identified by gas chromatography-mass spectrum (GC-MS), and SwissADME screened their physicochemical properties. Read More

View Article and Full-Text PDF
September 2021

Machine Learning-Enabled Pipeline for Large-Scale Virtual Drug Screening.

J Chem Inf Model 2021 Aug 17. Epub 2021 Aug 17.

Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.

Virtual screening is receiving renewed attention in drug discovery, but progress is hampered by challenges on two fronts: handling the ever-increasing sizes of libraries of drug-like compounds and separating true positives from false positives. Here, we developed a machine learning-enabled pipeline for large-scale virtual screening that promises breakthroughs on both fronts. By clustering compounds according to molecular properties and limited docking against a drug target, the full library was trimmed by 10-fold; the remaining compounds were then screened individually by docking; and finally, a dense neural network was trained to classify the hits into true and false positives. Read More

View Article and Full-Text PDF

Identification of lead compounds from large natural product library targeting 3C-like protease of SARS-CoV-2 using E-pharmacophore modelling, QSAR and molecular dynamics simulation.

In Silico Pharmacol 2021 7;9(1):49. Epub 2021 Aug 7.

Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, P.M.B. 704, Akure, 360001 Ondo State Nigeria.

COVID-19 is a novel disease caused by SARS-CoV-2 and has made a catastrophic impact on the global economy. As it is, there is no officially FDA approved drug to alleviate the negative impact of SARS-CoV-2 on human health. Numerous drug targets for neutralizing coronavirus infection have been identified, among them is 3-chymotrypsin-like-protease (3CL), a viral protease responsible for the viral replication is chosen for this study. Read More

View Article and Full-Text PDF

Progress in nasal drug delivery systems.

Int J Pharm 2021 Aug 12;607:120994. Epub 2021 Aug 12.

Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

Most of the available drugs are usually administered orally (e.g. in tablets or capsules) or by parenteral injection in the case of substances being destroyed in the gastric environment or not being absorbed. Read More

View Article and Full-Text PDF

An end-to-end automated platform process for high-throughput engineering of next-generation multi-specific antibody therapeutics.

MAbs 2021 Jan-Dec;13(1):1955433

R&D Large Molecules Research Platform Germany, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt Am Main, Germany.

Next-generation multi-specific antibody therapeutics (MSATs) are engineered to combine several functional activities into one molecule to provide higher efficacy compared to conventional, mono-specific antibody therapeutics. However, highly engineered MSATs frequently display poor yields and less favorable drug-like properties (DLPs), which can adversely affect their development. Systematic screening of a large panel of MSAT variants in very high throughput (HT) is thus critical to identify potent molecule candidates with good yield and DLPs early in the discovery process. Read More

View Article and Full-Text PDF

Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

J Med Chem 2021 Aug 12;64(16):12109-12131. Epub 2021 Aug 12.

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.

Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, , that binds with β-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. Read More

View Article and Full-Text PDF

Properties of peptides released from salmon and carp via simulated human-like gastrointestinal digestion described applying quantitative parameters.

PLoS One 2021 10;16(8):e0255969. Epub 2021 Aug 10.

Faculty of Food Science, Department of Dairy Science and Quality Management, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.

Apart from the classical (experimental) methods, biologically active peptides can be studied via bioinformatics approach, also known as in silico analysis. This study aimed to verify the following research hypothesis: ACE inhibitors and antioxidant peptides can be released from salmon and carp proteins during simulated in silico human-like gastrointestinal digestion. The potential to release biopeptides was evaluated using the BIOPEP-UWM quantitative criteria including the profile of biological activity, frequency of the occurrence (A)/release (AE) of fragments with an ACE inhibitory or antioxidant activity by selected enzymes, and relative frequency of release of bioactive fragments with a given activity by selected enzymes (W). Read More

View Article and Full-Text PDF

Fragment-type 4-azolylcoumarin derivatives with anticancer properties.

Arch Pharm (Weinheim) 2021 Aug 10:e2100238. Epub 2021 Aug 10.

Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Several coumarin derivatives with a directly attached azole substituent at C-4 were synthesized and biologically studied for their anticancer properties. The cell lines used for this investigation (HeLa, K-562, MDA-MB-53, and MCF-7) demonstrated different sensitivities. The best response in the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay was shown by K-562 cells, with compounds displaying activity (3c, IC 3. Read More

View Article and Full-Text PDF