Small Molecules as PD-1/PD-L1 Pathway Modulators for Cancer Immunotherapy

2019 ◽  
Vol 24 (41) ◽  
pp. 4911-4920 ◽  
Author(s):  
Peifu Jiao ◽  
Qiaohong Geng ◽  
Peng Jin ◽  
Gaoxing Su ◽  
Houyun Teng ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Immunotherapy ◽  
Therapeutic Antibodies ◽  
Manufacturing Costs ◽  
Tumor Penetration ◽  
Chemical Structures ◽  
Structure Activity ◽  
Cancer Models ◽  
Alternative Approach ◽  
Intracellular Targets

Blockade of PD-1/PD-L1 interactions using PD-1/PD-L1 pathway modulators has shown unprecedented clinical efficacy in various cancer models. Current PD-1/PD-L1 modulators approved by FDA are exclusively dominated by therapeutic antibodies. Nevertheless, therapeutic antibodies also exhibit several disadvantages such as low tumor penetration, difficulty in crossing physiological barriers, lacking oral bioavailability, high manufacturing costs, inaccessible to intracellular targets, immunogenicity, immune-related adverse events (irAEs). Modulation of PD-1/PD-L1 pathway using small molecules may be an alternative approach to mobilize immune system to fight against cancers. In this review, we focus on summarizing the recently disclosed chemical structures and preliminary structure-activity relationships (SARs) of small molecules as PD-1/PD-L1 modulators for cancer immunotherapy.

scholarly journals The Study on the hERG Blocker Prediction Using Chemical Fingerprint Analysis

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2615 ◽  
Author(s):  
Kwang-Eun Choi ◽  
Anand Balupuri ◽  
Nam Sook Kang
Keyword(s):  
Small Molecules ◽  
Quantitative Structure Activity Relationship ◽  
Training Set ◽  
Cardiac Side Effects ◽  
Chemical Structures ◽  
Structure Activity ◽  
Channel Blockage ◽  
Qsar Models ◽  
Herg Channels ◽  
Selection Of

Human ether-a-go-go-related gene (hERG) potassium channel blockage by small molecules may cause severe cardiac side effects. Thus, it is crucial to screen compounds for activity on the hERG channels early in the drug discovery process. In this study, we collected 5299 hERG inhibitors with diverse chemical structures from a number of sources. Based on this dataset, we evaluated different machine learning (ML) and deep learning (DL) algorithms using various integer and binary type fingerprints. A training set of 3991 compounds was used to develop quantitative structure–activity relationship (QSAR) models. The performance of the developed models was evaluated using a test set of 998 compounds. Models were further validated using external set 1 (263 compounds) and external set 2 (47 compounds). Overall, models with integer type fingerprints showed better performance than models with no fingerprints, converted binary type fingerprints or original binary type fingerprints. Comparison of ML and DL algorithms revealed that integer type fingerprints are suitable for ML, whereas binary type fingerprints are suitable for DL. The outcomes of this study indicate that the rational selection of fingerprints is important for hERG blocker prediction.

scholarly journals BIOSIMILARS IN INFLAMMATORY BOWEL DISEASES: an important moment for Brazilian gastroenterologists

2015 ◽  
Vol 52 (1) ◽  
pp. 76-80 ◽  
Author(s):  
Fábio Vieira TEIXEIRA ◽  
Paulo Gustavo KOTZE ◽  
Aderson Omar Mourão Cintra DAMIÃO ◽  
Sender Jankiel MISZPUTEN
Keyword(s):  
Small Molecules ◽  
Inflammatory Bowel Diseases ◽  
Generic Drugs ◽  
Specific Data ◽  
Chemical Structures ◽  
Bowel Diseases ◽  
Original Product ◽  
Inflammatory Bowel ◽  
The One ◽  
Extrapolation Of Indications

ABSTRACT Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn’s disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario.

scholarly journals PD-L1 Targeting Immune-Microbubble Complex Enhances Therapeutic Index in Murine Colon Cancer Models

2020 ◽  
Vol 14 (1) ◽  
pp. 6
Author(s):  
Daehyun Kim ◽  
Seung Soo Lee ◽  
Hyungwon Moon ◽  
So Yeon Park ◽  
Hak Jong Lee
Keyword(s):  
Cancer Immunotherapy ◽  
Focused Ultrasound ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Therapeutic Index ◽  
Treatment Regimens ◽  
Cancer Models ◽  
Programmed Death ◽  
Murine Colon ◽  
Cell Death Protein

Cancer immunotherapy has revolutionized the way different neoplasms are treated. Among the different variations of cancer immunotherapy, the checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have been validated and are currently used in the clinics. Nevertheless, these therapeutic antibodies are associated with significant side effects and are known to induce immune-related toxicities. To address these issues, we have developed an immune-microbubble complex (IMC) which not only reduces the toxicities associated with the antibodies but also enhances the therapeutic efficacy when combined with focused ultrasound. The concept of IMCs could be applied to any type of antibody-based treatment regimens to maximize their therapeutic potential.

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

Quantitative Structure Activity Relationship (QSAR) study predicts small molecule binding to RNA structure

2021 ◽  
Author(s):  
Zhengguo Cai ◽  
Martina Zafferani ◽  
Olanrewaju Akande ◽  
Amanda Hargrove
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structure ◽  
Quantitative Structure ◽  
Rna Structures ◽  
Qsar Study ◽  
Structure Activity ◽  
Qsar Models ◽  
Hiv 1

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSAR). Herein, we developed QSAR models that quantitatively predict both thermodynamic and kinetic-based binding parameters of small molecules and the HIV-1 TAR model RNA system. A set of small molecules bearing diverse scaffolds was screened against the HIV-1-TAR construct using surface plasmon resonance, which provided the binding kinetics and affinities. The data was then analyzed using multiple linear regression (MLR) combined with feature selection to afford robust models for binding of diverse RNA-targeted scaffolds. The predictivity of the model was validated on untested small molecules. The QSAR models presented herein represent the first application of validated and predictive 2D-QSAR using multiple scaffolds against an RNA target. We expect the workflow to be generally applicable to other RNA structures, ultimately providing essential insight into the small molecule descriptors that drive selective binding interactions and, consequently, providing a platform that can exponentially increase the efficiency of ligand design and optimization without the need for high-resolution RNA structures.

scholarly journals Structure-Dependent Activity of Plant-Derived Sweeteners

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1946 ◽  
Author(s):  
Serhat Sezai Ҫiçek
Keyword(s):  
Structural Biology ◽  
Binding Sites ◽  
Taste Receptor ◽  
Sweet Taste ◽  
Chemical Structures ◽  
Sweet Taste Receptor ◽  
Structure Activity ◽  
Dependent Activity ◽  
Diabetes And Obesity ◽  
Synthetic Derivatives

Human sensation for sweet tastes and the thus resulting over-consumption of sugar in recent decades has led to an increasing number of people suffering from caries, diabetes, and obesity. Therefore, a demand for sugar substitutes has arisen, which increasingly has turned towards natural sweeteners over the last 20 years. In the same period, thanks to advances in bioinformatics and structural biology, understanding of the sweet taste receptor and its different binding sites has made significant progress, thus explaining the various chemical structures found for sweet tasting molecules. The present review summarizes the data on natural sweeteners and their most important (semi-synthetic) derivatives until the end of 2019 and discusses their structure–activity relationships, with an emphasis on small-molecule high-intensity sweeteners.

scholarly journals Prediction of Terpenoid Toxicity Based on a Quantitative Structure–Activity Relationship Model

Foods ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 628 ◽  
Author(s):  
Rosa Perestrelo ◽  
Catarina Silva ◽  
Miguel X. Fernandes ◽  
José S. Câmara
Keyword(s):  
Vibrio Fischeri ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Partial Charge ◽  
Quantitative Structure ◽  
Chemical Structures ◽  
Structure Activity ◽  
Qsar Models ◽  
Toxicity Level

Terpenoids, including monoterpenoids (C10), norisoprenoids (C13), and sesquiterpenoids (C15), constitute a large group of plant-derived naturally occurring secondary metabolites with highly diverse chemical structures. A quantitative structure–activity relationship (QSAR) model to predict terpenoid toxicity and to evaluate the influence of their chemical structures was developed in this study by assessing in real time the toxicity of 27 terpenoid standards using the Gram-negative bioluminescent Vibrio fischeri. Under the test conditions, at a concentration of 1 µM, the terpenoids showed a toxicity level lower than 5%, with the exception of geraniol, citral, (S)-citronellal, geranic acid, (±)-α-terpinyl acetate, and geranyl acetone. Moreover, the standards tested displayed a toxicity level higher than 30% at concentrations of 50–100 µM, with the exception of (+)-valencene, eucalyptol, (+)-borneol, guaiazulene, β-caryophellene, and linalool oxide. Regarding the functional group, terpenoid toxicity was observed in the following order: alcohol > aldehyde ~ ketone > ester > hydrocarbons. The CODESSA software was employed to develop QSAR models based on the correlation of terpenoid toxicity and a pool of descriptors related to each chemical structure. The QSAR models, based on t-test values, showed that terpenoid toxicity was mainly attributed to geometric (e.g., asphericity) and electronic (e.g., maximum partial charge for a carbon (C) atom (Zefirov’s partial charge (PC)) descriptors. Statistically, the most significant overall correlation was the four-parameter equation with a training coefficient and test coefficient correlation higher than 0.810 and 0.535, respectively, and a square coefficient of cross-validation (Q2) higher than 0.689. According to the obtained data, the QSAR models are suitable and rapid tools to predict terpenoid toxicity in a diversity of food products.

scholarly journals Recent Advances in One-Pot Modular Synthesis of 2-Quinolones

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5450
Author(s):  
Wan Pyo Hong ◽  
Inji Shin ◽  
Hee Nam Lim
Keyword(s):  
Reaction Mechanism ◽  
Small Molecules ◽  
Functional Materials ◽  
Synthetic Methods ◽  
Microwave Irradiation Method ◽  
One Pot ◽  
Bond Forming ◽  
Chemical Structures ◽  
The Core ◽  
Modular Synthesis

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.

Bioactivities of Natural Catalpol Derivatives

2019 ◽  
Vol 26 (33) ◽  
pp. 6149-6173 ◽  
Author(s):  
Liu-Qiang Zhang ◽  
Kai-Xian Chen ◽  
Yi-Ming Li
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Inhibitory Potency ◽  
Pharmacological Activities ◽  
Chemical Structures ◽  
Naturally Occurring ◽  
Structure Activity ◽  
Extensive Coverage ◽  
Relationship Of

Catalpol, a famous molecule of iridoids, possesses extensive pharmacological activities. Our studies found that compounds with low-polarity substituents at the 6-O position of catalpol exhibited higher NF-κB inhibitory potency than catalpol. However, catalpol derivatives are not much focused. Here this review provides extensive coverage of naturally occurring catalpol derivatives discovered from 1888 until 2018. It covers their distribution, chemotaxonomic significance, chemical structures, and bioactivities from more than 200 peer-reviewed articles, and highlights the structure-activity relationship of catalpol derivatives.

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