scholarly journals Lead Evolution in Development of an Anti-allergic Agent; Dimethyl(2-phenoxyethyl)sulfonium p-Toluenesulfonate as the Secondary Lead Compound

2002 ◽  
Vol 2 ◽  
pp. 86-94 ◽  
Author(s):  
Yukio Tada ◽  
Ichiro Yamawaki ◽  
Shuichi Ueda ◽  
Hiroshi Matsumoto ◽  
Naosuke Matsuura ◽  
...  
Keyword(s):  
Lead Compound ◽  
Lead Evolution

Investigations on the main neolignan constituent methylhonokiol of Magnolia grandiflora as a new anti-inflammatory lead compound

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
W Schühly ◽  
A Hüfner ◽  
EM Wenzig ◽  
O Kunert ◽  
E Haslinger ◽  
...  
Keyword(s):  
Lead Compound ◽  
Magnolia Grandiflora ◽  
Anti Inflammatory

Automated, Accurate, and Scalable Relative Protein-Ligand Binding Free Energy Calculations using Lambda Dynamics

2020 ◽  
Author(s):  
E. Prabhu Raman ◽  
Thomas J. Paul ◽  
Ryan L. Hayes ◽  
Charles L. Brooks III
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Computational Cost ◽  
Combinatorial Libraries ◽  
Free Energy Calculations ◽  
Lead Optimization ◽  
Efficient Estimation ◽  
Lead Compound

<p>Accurate predictions of changes to protein-ligand binding affinity in response to chemical modifications are of utility in small molecule lead optimization. Relative free energy perturbation (FEP) approaches are one of the most widely utilized for this goal, but involve significant computational cost, thus limiting their application to small sets of compounds. Lambda dynamics, also rigorously based on the principles of statistical mechanics, provides a more efficient alternative. In this paper, we describe the development of a workflow to setup, execute, and analyze Multi-Site Lambda Dynamics (MSLD) calculations run on GPUs with CHARMm implemented in BIOVIA Discovery Studio and Pipeline Pilot. The workflow establishes a framework for setting up simulation systems for exploratory screening of modifications to a lead compound, enabling the calculation of relative binding affinities of combinatorial libraries. To validate the workflow, a diverse dataset of congeneric ligands for seven proteins with experimental binding affinity data is examined. A protocol to automatically tailor fit biasing potentials iteratively to flatten the free energy landscape of any MSLD system is developed that enhances sampling and allows for efficient estimation of free energy differences. The protocol is first validated on a large number of ligand subsets that model diverse substituents, which shows accurate and reliable performance. The scalability of the workflow is also tested to screen more than a hundred ligands modeled in a single system, which also resulted in accurate predictions. With a cumulative sampling time of 150ns or less, the method results in average unsigned errors of under 1 kcal/mol in most cases for both small and large combinatorial libraries. For the multi-site systems examined, the method is estimated to be more than an order of magnitude more efficient than contemporary FEP applications. The results thus demonstrate the utility of the presented MSLD workflow to efficiently screen combinatorial libraries and explore chemical space around a lead compound, and thus are of utility in lead optimization.</p>

Naldemedine: Peripherally Acting Opioid Receptor Antagonist for Treating Opioid-induced Adverse Effects

2020 ◽  
Vol 20 (31) ◽  
pp. 2830-2842
Author(s):  
Masanao Inagaki ◽  
Toshiyuki Kanemasa ◽  
Takaaki Yokota
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Severe Pain ◽  
Lead Compound ◽  
Inhibitory Effects ◽  
Pharmacokinetic Profiles ◽  
Structure Activity ◽  
The Usa ◽  
Relationship Study ◽  
The Eu

Opioids are widely used for pain management in moderate-to-severe pain. However, opioids are associated with adverse events, such as constipation and emesis/vomiting. To reduce these undesired effects, a structure–activity relationship study of morphinan derivatives was conducted, and a promising lead compound with inhibitory effects on opioid receptors was obtained. Further improvement in the potency and pharmacokinetic profiles of the lead compound led to the discovery of naldemedine, which showed anti-constipation and anti-emetic effects against these adverse events that were induced by morphine without influencing morphine’s analgesic effect. Naldemedine was launched in Japan and the USA in 2017 and in the EU in 2019, for treating opioid-induced constipation.

Design, Synthesis and Antifungal Activity of Novel 1-(Adamantan-1-yl) ethanone Oxime Esters

2020 ◽  
Vol 17 (5) ◽  
pp. 526-532
Author(s):  
Si Liu ◽  
Li-Zhi Niu ◽  
Yan-Hua Shi ◽  
Fu-Xian Wan ◽  
Lin Jiang
Keyword(s):  
Antifungal Activity ◽  
Biological Activities ◽  
Lead Compound ◽  
Design Synthesis ◽  
Antifungal Activities

Background: Oxime compounds, including oxime ethers and oxime esters, possess various biological activities. Many oxime ethers have been widely used in the fields of pesticides and medicines. However, oxime ethers are rarely used in the field of pesticides. Methods: We chose the excellent fungicide pyrifenox as the lead compound, integrated pyridinyl, adamantyl and benzoyl moieties into one molecule, while also designed and synthesized ten 1- (adamantan-1-yl)ethanone oxime esters containing pyridinyl moiety. Moreover, we also evaluated their preliminary antifungal activities against S. sclerotiorum and B. cinerea. Results: The target compounds were characterized by NMR, IR and HRMS. The preliminary bioactivity test showed that they exhibited some antifungal activity to S. sclerotiorum and B. cinerea, and EC50 values were in the range of 14.16-32.97 and 27.60-52.82 μg/mL, respectively. Conclusion: Some target compounds such as 3d, 3e, 3h and 3i, exhibited moderate activities against S. sclerotiorum, with EC50 values of 14.16-18.18 μg/mL.

scholarly journals COVID-19 Vaccination: From Interesting Agent to the Patient

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 120
Author(s):  
Anis Daou
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gastrointestinal Tract ◽  
Circulatory System ◽  
The Novel ◽  
Lead Compound ◽  
Fda Approval ◽  
The World ◽  
The Central Nervous System ◽  
Novel Coronavirus

The vaccination for the novel Coronavirus (COVID-19) is undergoing its final stages of analysis and testing. It is an impressive feat under the circumstances that we are on the verge of a potential breakthrough vaccination. This will help reduce the stress for millions of people around the globe, helping to restore worldwide normalcy. In this review, the analysis looks into how the new branch of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) came into the forefront of the world like a pandemic. This review will break down the details of what COVID-19 is, the viral family it belongs to and its background of how this family of viruses alters bodily functions by attacking vital human respiratory organs, the circulatory system, the central nervous system and the gastrointestinal tract. This review also looks at the process a new drug analogue undergoes, from (i) being a promising lead compound to (ii) being released into the market, from the drug development and discovery stage right through to FDA approval and aftermarket research. This review also addresses viable reasoning as to why the SARS-CoV-2 vaccine may have taken much less time than normal in order for it to be released for use.

scholarly journals Racemization-free synthesis of Nα-2-thiophenoyl-phenylalanine-2-morpholinoanilide enantiomers and their antimycobacterial activity

Amino Acids ◽  
2021 ◽  
Author(s):  
Lea Mann ◽  
Markus Lang ◽  
Philipp Schulze ◽  
Jan Henrik Halz ◽  
René Csuk ◽  
...  
Keyword(s):  
Title Compound ◽  
Mammalian Cells ◽  
Antimycobacterial Activity ◽  
Lead Compound ◽  
Coupling Reagents ◽  
Hydrogen Bonding Interactions ◽  
Amide Coupling ◽  
Subsequent Separation ◽  
Synthetic Routes ◽  
Insight Into

AbstractNα-2-thiophenoyl-d-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box® library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P® and PyBOP® amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from d-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.

An enumeration of natural products from microbial, marine and terrestrial sources

2020 ◽  
Vol 5 (8) ◽  
Author(s):  
Fidele Ntie-Kang ◽  
Daniel Svozil
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Biologically Active ◽  
Lead Compound ◽  
Chemical Databases ◽  
Natural Sources ◽  
Chemical Structures ◽  
Chemically Modified ◽  
Marine Habitats ◽  
Metabolic Properties

AbstractThe discovery of a new drug is a multidisciplinary and very costly task. One of the major steps is the identification of a lead compound, i.e. a compound with a certain degree of potency and that can be chemically modified to improve its activity, metabolic properties, and pharmacokinetics profiles. Terrestrial sources (plants and fungi), microbes and marine organisms are abundant resources for the discovery of new structurally diverse and biologically active compounds. In this chapter, an attempt has been made to quantify the numbers of known published chemical structures (available in chemical databases) from natural sources. Emphasis has been laid on the number of unique compounds, the most abundant compound classes and the distribution of compounds in terrestrial and marine habitats. It was observed, from the recent investigations, that ~500,000 known natural products (NPs) exist in the literature. About 70 % of all NPs come from plants, terpenoids being the most represented compound class (except in bacteria, where amino acids, peptides, and polyketides are the most abundant compound classes). About 2,000 NPs have been co-crystallized in PDB structures.

scholarly journals Synthesis and Biological Evaluation of Hydroxylated Monocarbonyl Curcumin Derivatives as Potential Inducers of Neprilysin Activity

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 955
Author(s):  
Dimitris Matiadis ◽  
See-Ting Ng ◽  
Eric H.-L. Chen ◽  
Georgia Nigianni ◽  
Veroniki P. Vidali ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Therapeutic Strategy ◽  
Specific Inhibitor ◽  
Biological Evaluation ◽  
Lead Compound ◽  
Cleavage Activity ◽  
Curcumin Derivatives ◽  
Aβ Clearance ◽  
Activity Enhancement ◽  
Synthesis And Biological Evaluation

Background: Alzheimer’s disease (AD) involves impairment of Aβ clearance. Neprilysin (NEP) is the most efficient Aβ peptidase. Enhancement of the activity or expression of NEP may provide a prominent therapeutic strategy against AD. Aims: Ten hydroxylated monocarbonyl curcumin derivatives were designed, synthesized and evaluated for their NEP upregulating potential using sensitive fluorescence-based Aβ digestion and inhibition assays. Results: Compound 4 was the most active one, resulting in a 50% increase in Aβ cleavage activity. Cyclohexanone-bearing derivatives exhibited higher activity enhancement compared to their acetone counterparts. Inhibition experiments with the NEP-specific inhibitor thiorphan resulted in dramatic cleavage reduction. Conclusion: The increased Aβ cleavage activity and the ease of synthesis of 4 renders it an extremely attractive lead compound.

scholarly journals Triterpenoids from Argania spinosa: 20 Years of Research

2013 ◽  
Vol 8 (1) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Imane Chafchaouni-Moussaoui ◽  
Zoubida Charrouf ◽  
Dom Guillaume
Keyword(s):  
Research Evidence ◽  
Economic Potential ◽  
Lead Compound ◽  
Argania Spinosa ◽  
Argan Oil ◽  
Argan Tree ◽  
Phytochemical Investigation ◽  
The World ◽  
The Subject

During the last two decades, the argan tree has been the subject of intensive phytochemical investigation. If argan oil is the most known argan derivative, argan saponins are frequently considered as molecules presenting a strong economic potential. This review presents an update of the current research efforts on argan saponins from around the world. Research evidence suggests that arganine C can be considered as a lead compound for new antivirals.

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