149 results match your criteria greater drug-like

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

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Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability.

J Med Chem 2021 Sep 26;64(17):12705-12722. Epub 2021 Aug 26.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the enzyme as a critical endogenous cerebroprotective mechanism and validated target for the treatment of ischemic stroke. Overexpression of Nln in a mouse model of stroke results in dramatic improvement of stroke outcomes, while pharmacological inhibition aggravates them. Read More

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September 2021


J Pharmacol Exp Ther 2021 Aug 13. Epub 2021 Aug 13.

Pharmaceutical Sciences, School of Pharmacy, TTUHSC, United States

Neurolysin (Nln) is a recently recognized endogenous mechanism functioning to preserve the brain from ischemic injury. To further understand the pathophysiological function of this peptidase in stroke and other neurological disorders, the present study was designed to identify small molecule activators of Nln. Using a computational approach, the structure of Nln was explored, followed by docking and screening of ~140,000 molecules from the National Cancer Institute Developmental Therapeutics Program database. Read More

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Development of 2-Morpholino-N-hydroxybenzamides as anti-proliferative PC-PLC inhibitors.

Bioorg Chem 2021 Sep 7;114:105152. Epub 2021 Jul 7.

School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand. Electronic address:

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a key enzyme involved in the metabolism of the mammalian phospholipid phosphatidylcholine into secondary messengers diacylglycerol (DAG) and phosphocholine. DAG and phosphocholine have been identified to amplify various cellular processes involved in oncogenesis such as proliferation, cell-cycle activation, differentiation and motility, therefore making PC-PLC a potential target for novel anti-cancer treatments. The current literature standard for PC-PLC inhibition, tricyclodecan-9-yl-potassium xanthate (D609), has been shown to arrest proliferation in multiple cancer cell lines, however, it is not drug-like resulting in low aqueous stability, making it a poor drug candidate. Read More

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September 2021

Synthetic fluorescent MYC probe: Inhibitor binding site elucidation and development of a high-throughput screening assay.

Bioorg Med Chem 2021 Jul 6;42:116246. Epub 2021 Jun 6.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States. Electronic address:

We report the discovery of a fluorescent small molecule probe. This probe exhibits an emission increase in the presence of the oncoprotein MYC that can be attenuated by a competing inhibitor. Hydrogen-deuterium exchange mass spectrometry analysis, rationalized by induced-fit docking, suggests it binds to the "coiled-coil" region of the leucine zipper domain. Read More

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Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs.

Bioorg Med Chem Lett 2021 Aug 29;46:128162. Epub 2021 May 29.

Human BioMolecular Research Institute, 6351 Nancy Ridge Dr. Suite B, San Diego, CA 92121, USA. Electronic address:

In the United States, approximately one million individuals are hospitalized every year for arrhythmias, making arrhythmias one of the top causes of healthcare expenditures. Mexiletine is currently used as an antiarrhythmic drug but has limitations. The purpose of this work was to use normal and Long QT syndrome Type 3 (LQTS3) patient-derived human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify an analog of mexiletine with superior drug-like properties. Read More

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The Good, the Bad, and the Twisted Revisited: An Analysis of Ligand Geometry in Highly Resolved Protein-Ligand X-ray Structures.

J Med Chem 2021 06 1;64(11):7533-7543. Epub 2021 Jun 1.

Skilos Chemoinformatics, 159 Water Street, Cambridge CB4 1PB, United Kingdom.

An analysis of the rotatable bond geometry of drug-like ligand models is reported for high-resolution (<1.1 Å) crystallographic protein-ligand complexes. In cases where the ligand fit to the electron density is very good, unusual torsional geometry is rare and, most often, though not exclusively, associated with strong polar, metal, or covalent ligand-protein interactions. Read More

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Target-Based Evaluation of "Drug-Like" Properties and Ligand Efficiencies.

J Med Chem 2021 06 13;64(11):7210-7230. Epub 2021 May 13.

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, United Kingdom.

Physicochemical descriptors commonly used to define "drug-likeness" and ligand efficiency measures are assessed for their ability to differentiate marketed drugs from compounds reported to bind to their efficacious target or targets. Using ChEMBL version 26, a data set of 643 drugs acting on 271 targets was assembled, comprising 1104 drug-target pairs having ≥100 published compounds per target. Taking into account changes in their physicochemical properties over time, drugs are analyzed according to their target class, therapy area, and route of administration. Read More

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Design, Synthesis, Biological Evaluation and In Silico Studies of Pyrazole-Based NH-Acyl Oseltamivir Analogues as Potent Neuraminidase Inhibitors.

Pharmaceuticals (Basel) 2021 Apr 16;14(4). Epub 2021 Apr 16.

State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.

Oseltamivir represents one of the most successful neuraminidase (NA) inhibitors in the current anti-influenza therapy. The 150-cavity of NA was identified as an additional binding pocket, and novel NA inhibitors have been designed to occupy the 150-cavity based on the structure information of oseltamivir carboxylate () in complex with NA. In this study, a series of C-5-NH-acyl derivatives of containing the pyrazole moiety were synthesized. Read More

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Virtual discovery of a hetero-cyclic compound from the Universal Natural Product Database (UNPD36) as a potential inhibitor of interleukin-33: molecular docking and dynamic simulations.

J Biomol Struct Dyn 2021 Apr 24:1-10. Epub 2021 Apr 24.

Complex Systems Division, Beijing Computational Science Research Center, Beijing, China.

Interleukin (IL)-33 is a cytokine implicated in several inflammatory and autoimmune diseases. Upon binding to its receptor ST2, IL-33 activates allergic inflammatory responses. To block this protein-protein interaction with a potential anti-allergic agent, we screened Universal Natural Product Database (UNPD) using a combined approach of molecular docking and dynamic simulations. Read More

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In-silico pharmacophoric and molecular docking-based drug discovery against the Main Protease (Mpro) of SARS-CoV-2, a causative agent COVID-19.

Pak J Pharm Sci 2020 Nov;33(6):2697-2705

Centre for Agricultural Biochemistry and Biotechnology (CABB), University of Agriculture Faisalabad (UAF), Faisalabad, Pakistan.

COVID-19 (Coronavirus Disease 2019) caused by a novel 'SARS-CoV-2' virus resulted in public health emergencies across the world. An effective vaccine to cure this virus is not yet available, thus requires concerted efforts at various scales. In this study, we employed Computer-Aided Drug Design (CADD) based approach to identify the drug-like compounds - inhibiting the replication of the main protease (M) of SARS-CoV-2. Read More

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November 2020

Do Drug-likeness Rules Apply to Oral Prodrugs?

ChemMedChem 2021 May 25;16(9):1446-1456. Epub 2021 Feb 25.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 Pampulha, Belo Horizonte, MG, BR 31270-901, Brazil.

This paper describes a comparative analysis of the physicochemical and structural properties of prodrugs and their corresponding drugs with regard to drug-likeness rules. The dataset used in this work was obtained from the DrugBank. Sixty-five pairs of prodrugs/drugs were retrieved and divided into the following categories: carrier-linked to increase hydrophilic character, carrier-linked to increase absorption, and bioprecursors. Read More

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Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity.

J Pharmacol Exp Ther 2021 03 16;376(3):397-409. Epub 2020 Dec 16.

EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Billerica, Massachusetts (J.V., A.T.B., M.P., A.P., A.D., T.J., E.T., N.T.M., S.F.Z., S.L.O., R.W., B.S.) and Merck KGaA, Darmstadt, Germany (S.R., D.M., P.H.).

Toll-like receptor (TLR) 7 and TLR8 are transmembrane receptors that recognize single-stranded RNA. Activation of these receptors results in immune cell stimulation and inflammatory cytokine production, which is normally a protective host response. However, aberrant activation of TLR7/8 is potentially pathogenic and linked to progression of certain autoimmune diseases such as lupus. Read More

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Identification of potential drug target in malarial disease using molecular docking analysis.

Saudi J Biol Sci 2020 Dec 16;27(12):3327-3333. Epub 2020 Oct 16.

Faculty of Agricultural Sciences, University of Gezira, Wad-Medani, P.O Box 20, Sudan.

Malaria caused by genus a parasite which is the main health issue for humans and about half of the population were suffered. An every year, approximately 1.2-2. Read More

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December 2020

Identification of a novel and potent small molecule inhibitor of SRPK1: mechanism of dual inhibition of SRPK1 for the inhibition of cancer progression.

Aging (Albany NY) 2020 12 3;13(1):163-180. Epub 2020 Dec 3.

School of Biotechnology, Gautam Buddha University, Greater Noida, U.P. 201312, India.

Protein kinases are the family of attractive enzyme targets for drug design with relevance to cancer biology. Serine arginine protein kinase 1 (SRPK1) is responsible for the phosphorylation of serine/arginine (SR)-rich proteins. Alternative Splicing Factor/Splicing Factor 2 (ASF/SF2) involved in mRNA editing. Read More

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December 2020

A molecular dynamics and docking study to screen anti-cancer compounds targeting mutated p53.

J Biomol Struct Dyn 2020 Oct 28:1-10. Epub 2020 Oct 28.

College of Engineering, IT and Environment, Charles Darwin University, Darwin, Australia.

The p53 gene is mutated in greater than 50% of several human cancers including bladder urothelial carcinoma, lung adenocarcinoma, colorectal carcinoma, and oral cancer. Mutations in the p53 gene occur predominantly in the DNA-binding domain causing loss of function and accumulation of dysfunctional p53 protein in tumors by hetero-oligomerization with the wild type p53. Thus an in silico approach for the rational design of potent, pharmacologically active small drug-like compounds targeting mutated p53 was undertaken. Read More

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October 2020

Identification of promising molecules against MurD ligase from Acinetobacter baumannii: insights from comparative protein modelling, virtual screening, molecular dynamics simulations and MM/PBSA analysis.

J Mol Model 2020 Oct 17;26(11):304. Epub 2020 Oct 17.

Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, U.P., P.C. 201310, India.

Acinetobacter baumannii, an opportunistic bacterium of the multidrug-resistant (MDR) ESKAPE family of pathogens, is responsible for 2-10% infections associated with all gram-negative bacteria. The hospital-acquired nosocomial infections caused by A.baumannii include deadly diseases like ventilator-associated pneumonia, bacteremia, septicemia and urinary tract infections (UTI). Read More

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October 2020

Antiparasitic activities of novel pyrimidine N-acylhydrazone hybrids.

Drug Dev Res 2021 Apr 30;82(2):230-240. Epub 2020 Sep 30.

Departamento de Química, Universidade Estadual de Maringá (UEM), Maringá, Brazil.

In this article, a series of 29 new pyrimidine N-acylhydrazone hybrids were synthesized and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi protozoa that cause the neglected diseases cutaneous leishmaniasis and Chagas disease, respectively. Eight of the target compounds showed significant antiprotozoal activities with IC values in 4.3-33. Read More

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Detectives and helpers: Natural products as resources for chemical probes and compound libraries.

Pharmacol Ther 2020 12 25;216:107688. Epub 2020 Sep 25.

Department of Chemistry, Durham University, Lower Mount Joy, South Road, Durham DH1 3LE, UK. Electronic address:

About 70% of the drugs in use are derived from natural products, either used directly or in chemically modified form. Among all possible small molecules (not greater than 5 kDa), only a few of them are biologically active. Natural product libraries may have a higher rate of finding "hits" than synthetic libraries, even with the use of fewer compounds. Read More

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December 2020

In Silico Study Identified Methotrexate Analog as Potential Inhibitor of Drug Resistant Human Dihydrofolate Reductase for Cancer Therapeutics.

Molecules 2020 Jul 31;25(15). Epub 2020 Jul 31.

Division of Life Sciences, Division of Applied Life Science (BK21 Plus), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea.

Drug resistance is a core issue in cancer chemotherapy. A known folate antagonist, methotrexate (MTX) inhibits human dihydrofolate reductase (hDHFR), the enzyme responsible for the catalysis of 7,8-dihydrofolate reduction to 5,6,7,8-tetrahydrofolate, in biosynthesis and cell proliferation. Structural change in the DHFR enzyme is a significant cause of resistance and the subsequent loss of MTX. Read More

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Design, synthesis, and evaluation of 1, 4-benzodioxan-substituted chalcones as selective and reversible inhibitors of human monoamine oxidase B.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1513-1523

Department of Bioengineering, Zunyi Medical University, Zhuhai, China.

The inhibition of monoamine oxidase B (MAO-B) could be an effective approach for the treatment of various neurological disorders. In this study, a series of 1, 4-benzodioxan-substituted chalcone derivatives were designed, synthesised and evaluated for their inhibitory activity against human MAO-B (hMAO-B). The majority of these compounds showed inhibitory activity and high selectivity. Read More

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December 2020

Structure-Based Screening of DNA GyraseB Inhibitors for Therapeutic Applications in Tuberculosis: a Pharmacoinformatics Study.

Appl Biochem Biotechnol 2020 Dec 20;192(4):1107-1123. Epub 2020 Jul 20.

Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and considered as serious public health concern worldwide which kills approximately five thousand people every day. Therefore, TB drug development efforts are in gigantic need for identification of new potential chemical agents to eradicate TB from the society. The bacterial DNA gyrase B (GyrB) protein as an experimentally widely accepted effective drug target for the development of TB chemotherapeutics. Read More

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December 2020

Physicochemical and Pharmacokinetic Analysis of Anacardic Acid Derivatives.

ACS Omega 2020 Mar 13;5(11):6021-6030. Epub 2020 Mar 13.

Inorganic Materials Research Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India.

Anacardic acid (AA) and its derivatives are well-known for their therapeutic applications ranging from antitumor, antibacterial, antioxidant, anticancer, and so forth. However, their poor pharmacokinetic and safety properties create significant hurdles in the formulation of the final drug molecule. As a part of our endeavor to enhance the potential and exploration of the anticancer activities, a detailed study on the properties of selected AA derivatives was performed in this work. Read More

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Miniproteins as a Powerful Modality in Drug Development.

Trends Biochem Sci 2020 04 31;45(4):332-346. Epub 2020 Jan 31.

Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Room D4-100, Seattle, WA 98109, USA. Electronic address:

Miniproteins are a diverse group of protein scaffolds characterized by small (1-10 kDa) size, stability, and versatility in drug-like roles. Coming largely from native sources, they have been widely adopted into drug development pipelines. While their structures and capabilities are diverse, the approaches to their utilization share more similarities with each other than with more widely used modalities (e. Read More

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Chemical reactivity theory (CRT) study of small drug-like biologically active molecules.

Ruby Srivastava

J Biomol Struct Dyn 2021 Feb 11;39(3):943-952. Epub 2020 Feb 11.

Bioinformatics, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.

New biochemical screening and design based technology are used to identify the small molecules in targeting RNA. These approaches has develop potential drug like small molecule for RNA-targeted therapeutics. Chemical Reactivity Theory (CRT) is used to study these drug-like, biologically active small molecules that target RNA. Read More

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February 2021

Antibacterial activity of griseofulvin analogues as an example of drug repurposing.

Int J Antimicrob Agents 2020 Mar 10;55(3):105884. Epub 2020 Jan 10.

Institute of Biomedical Chemistry, Moscow, Russia.

Griseofulvin is a well-known antifungal drug that was launched in 1962 by Merck & Co. for the treatment of dermatophyte infections. However, according to predictions using the Way2Drug computational drug repurposing platform, it may also have antibacterial activity. Read More

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Interaction of Selected Terpenoids From With Catalytic Domain of Matrix Metalloproteinase-1: An In Silico Assessment of Their Anti-wrinkling Potential.

Bioinform Biol Insights 2019 24;13:1177932219896538. Epub 2019 Dec 24.

Agriculture Plant Biotechnology Lab (ARL-316), University School of Biotechnology, Guru Gobind Singh Indraprastha University, Sector-16 C, Dwarka, New Delhi-110078, India.

Matrix metalloproteinase-1 (MMP-1) is a predominant collagenase enzyme that cleaves collagen fibers, contributing to skin wrinkling. Matrix metalloproteinase-1 inhibitors of herbal origin may provide an earnest probability to offer a novel curative approach against MMP-1-mediated collagenolysis, prompted by ultraviolet (UV)-induced overexpression of MMP-1. In this in silico study, we have explored the MMP-1 inhibitory potential of selected terpenoids from extracts. Read More

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December 2019

Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.

Mol Pharm 2020 02 13;17(2):461-471. Epub 2020 Jan 13.

Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States.

Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. Read More

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February 2020

MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions.

Pharmacol Res Perspect 2019 12 2;7(6):e00547. Epub 2019 Dec 2.

Medicines Research Centre GlaxoSmithKline R&D Ltd Stevenage United Kingdom.

Activation of MrgX2, an orphan G protein-coupled receptor expressed on mast cells, leads to degranulation and histamine release. Human MrgX2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine-like adverse drug reactions of injected therapeutic agents. We set out to identify MrgX2 orthologues from other mammalian species used in nonclinical stages of drug development. Read More

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December 2019

Screening of promising molecules against MurG as drug target in multi-drug-resistant- - insights from comparative protein modeling, molecular docking and molecular dynamics simulation.

J Biomol Struct Dyn 2020 Oct 12;38(17):5230-5252. Epub 2019 Dec 12.

Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India.

The UDP--acetylglucosamine--acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol -acetylglucosamine transferase (MurG) is located in plasma membrane which plays a crucial role for peptidoglycan biosynthesis in Gram-negative bacteria. Recently, this protein is considered as an important and unique drug target in since it plays a key role during the synthesis of peptidoglycan as well as which is not found in In this study, initially we performed comparative protein modeling approach to predict the three-dimensional model of MurG based on crystal structure of UDP--acetylglucosamine--acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase (PDB ID: 1F0K) from K12. MurG model has two important functional domains located in and terminus which are separated by a deep cleft. Read More

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October 2020