scholarly journals HobPre: accurate prediction of human oral bioavailability for small molecules

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Min Wei ◽  
Xudong Zhang ◽  
Xiaolin Pan ◽  
Bo Wang ◽  
Changge Ji ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Oral Bioavailability ◽  
Computational Models ◽  
Experimental Tests ◽  
New Drugs ◽  
Drug Candidates ◽  
Drug Molecules ◽  
Key Factor ◽  
Input Variables

AbstractHuman oral bioavailability (HOB) is a key factor in determining the fate of new drugs in clinical trials. HOB is conventionally measured using expensive and time-consuming experimental tests. The use of computational models to evaluate HOB before the synthesis of new drugs will be beneficial to the drug development process. In this study, a total of 1588 drug molecules with HOB data were collected from the literature for the development of a classifying model that uses the consensus predictions of five random forest models. The consensus model shows excellent prediction accuracies on two independent test sets with two cutoffs of 20% and 50% for classification of molecules. The analysis of the importance of the input variables allowed the identification of the main molecular descriptors that affect the HOB class value. The model is available as a web server at www.icdrug.com/ICDrug/ADMET for quick assessment of oral bioavailability for small molecules. The results from this study provide an accurate and easy-to-use tool for screening of drug candidates based on HOB, which may be used to reduce the risk of failure in late stage of drug development. Graphical Abstract

scholarly journals Inter-individual variability and modeling of electrical activity: a possible new approach to explore cardiac safety?

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Jean-Yves Le Guennec ◽  
Jérôme Thireau ◽  
Aude Ouillé ◽  
Julien Roussel ◽  
Jérôme Roy ◽  
...  
Keyword(s):  
Side Effects ◽  
Computational Models ◽  
Simulation Models ◽  
Human Action ◽  
Individual Variability ◽  
New Drugs ◽  
Channel Blockers ◽  
Nucleotide Polymorphisms ◽  
Cardiac Side Effects ◽  
Drug Candidates

Abstract Safety pharmacology aims to predict rare side effects of new drugs. We explored whether rare pro-arrhythmic effects could be linked to the variability of the effects of these drugs on ion currents and whether taking into consideration this variability in computational models could help to better detect and predict cardiac side effects. For this purpose, we evaluated how intra- and inter-individual variability influences the effect of hERG inhibition on both the action potential duration and the occurrence of arrhythmias. Using two computer simulation models of human action potentials (endocardial and Purkinje cells), we analyzed the contribution of two biological parameters on the pro-arrhythmic effects of several hERG channel blockers: (i) spermine concentration, which varies with metabolic status, and (ii) L-type calcium conductance, which varies due to single nucleotide polymorphisms or mutations. By varying these parameters, we were able to induce arrhythmias in 1 out of 16 simulations although conventional modeling methods to detect pro-arrhythmic molecules failed. On the basis of our results, taking into consideration only 2 parameters subjected to intra- and inter-individual variability, we propose that in silico computer modeling may help to better define the risks of new drug candidates at early stages of pre-clinical development.

scholarly journals Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement

2020 ◽  
Author(s):  
Koichi Sasaki ◽  
Minori Harada ◽  
Takuma Yoshikawa ◽  
Hiroshi Tagawa ◽  
Yui Harada ◽  
...  
Keyword(s):  
Small Molecules ◽  
Folate Receptor ◽  
Specific Antigen ◽  
Target Cells ◽  
Lower Efficiency ◽  
Drug Candidates ◽  
Key Factor ◽  
Dependent Cell ◽  
Binding Antibody ◽  
Specific Membrane

<div> <div> <div> <p>Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing cancer cell elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate membrane-specific antigen but did so with lower efficiency compared with Fc-ARMs targeting folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy. </p> </div> </div> </div>

scholarly journals SMALL MOLECULES SOLVING BIG PROBLEMS: PRESENT AND FUTURE OF DRUG DISCOVERY

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna Lucia Fallacara ◽  
Iuni Margaret Laura Tris ◽  
Amalia Belfiore ◽  
Maurizio Botta
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Small Molecules ◽  
Rational Design ◽  
Development Process ◽  
New Drugs ◽  
Drug Development Process ◽  
Development Models ◽  
The Past ◽  
The Cost

The Drug development process has undergone a great change over the years. The way, from haphazard discovery of new natural products with a potent biological activity to a rational design of small molecule effective against a selected target, has been long and sprinkled with difficulties. The oldest drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even if the production of new drugs remains constant. The present paper, will give an overview of the principles, approaches, processes, and status of drug discovery today with an eye towards the past and the future.

Methods of Synthesis of Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine: Four Small Molecules Repurposed for Clinical Trials during the Covid-19 Pandemic

Synthesis ◽  
2020 ◽  
Vol 52 (24) ◽  
pp. 3735-3750 ◽  
Author(s):  
Nader Al Bujuq
Keyword(s):  
Small Molecules ◽  
New Drugs ◽  
Reference Source ◽  
The Novel ◽  
Efficacy And Safety ◽  
Health Measures ◽  
Drug Molecules ◽  
Agency Support ◽  
Methods Of Synthesis ◽  
Novel Coronavirus

AbstractThe novel coronavirus (COVID-19) disease has rapidly evolved into a sweeping pandemic despite public health measures. Screening and development of new vaccines and antivirals are expensive and time consuming. However, the repositioning of available drugs is an essential and universal strategy in the development of new drugs and therefore should receive priority attention as well as international government and agency support. Significant drugs such as chloroquine, hydroxychloroquine, favipiravir and remdesivir, are currently undergoing clinical studies to test their efficacy and safety. Some promising results have been achieved thus far in the treatment of COVID-19. In this article we summarize and discuss the most common synthetic strategies to apply in the preparation of these drug molecules. It is hoped that this compendium will provide an accessible useful guide and reference source for scientists, researchers and academia in their battle against COVD-19.1 Introduction2 Synthesis of Chloroquine (CQ) and Hydroxychloroquine (HCQ)2.1 Synthesis of 4,7-Dichloroquinoline 1 2.2 Synthesis of 2-Amino-5-(diethylamino)pentane (Novoldiamine) 2 2.3 Synthesis of 5-(N-Ethyl-N-2-hydroxyethylamino)-2-pentylamine 4 2.4 Developed Methods for Synthesis of Chloroquine and Hydroxychloroquine2.5 Synthesis of (R)-Chloroquine, (S)-Chloroquine, (R)-Hydroxychloroquine and (S)-Hydroxychloroquine3 Synthesis of Favipiravir (Avigan)4 Synthesis of Remdesivir5 Conclusion

scholarly journals Drug Repurposing Strategy (DRS): Emerging Approach to Identify Potential Therapeutics for Treatment of Novel Coronavirus Infection

2021 ◽  
Vol 8 ◽  
Author(s):  
Biswa Mohan Sahoo ◽  
B. V. V. Ravi Kumar ◽  
J. Sruti ◽  
Manoj Kumar Mahapatra ◽  
Bimal K. Banik ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Therapeutic Agents ◽  
Free Energy Calculations ◽  
Pharmacokinetic Property ◽  
The Novel ◽  
Drug Candidates ◽  
Drug Molecules

Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.

scholarly journals Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement

2020 ◽  
Author(s):  
Koichi Sasaki ◽  
Minori Harada ◽  
Takuma Yoshikawa ◽  
Hiroshi Tagawa ◽  
Yui Harada ◽  
...  
Keyword(s):  
Small Molecules ◽  
Folate Receptor ◽  
Specific Antigen ◽  
Target Cells ◽  
Lower Efficiency ◽  
Drug Candidates ◽  
Key Factor ◽  
Dependent Cell ◽  
Binding Antibody ◽  
Specific Membrane

<div> <div> <div> <p>Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing cancer cell elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate membrane-specific antigen but did so with lower efficiency compared with Fc-ARMs targeting folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy. </p> </div> </div> </div>

scholarly journals Frequency and Importance of Six Functional Groups that Play a Role in Drug Discovery

2018 ◽  
Vol 15 (3) ◽  
pp. 541-548
Author(s):  
Sholeh Maslehat ◽  
Soroush Sardari ◽  
Mahboube Ganji Arjenaki
Keyword(s):  
Small Molecules ◽  
Functional Groups ◽  
Functional Group ◽  
Molecular Data ◽  
New Drugs ◽  
Parent Molecule ◽  
Drug Molecules ◽  
Therapeutic Properties ◽  
The Common ◽  
Source Of Information

Small molecules are composed of chemical functional groups; they are sets of connected atoms or atom groups that determine properties and reactivity of the parent molecule. DrugBank is a rich source of information that containing molecular data about small molecules, their mechanisms, pharmaceutical interaction and targets. In this study, After collecting data of small drug molecules from DrugBank database and classifying them in different categories based on their mechanism of action, the therapeutic properties of the molecules were recorded. Finally, the functional group from the pharmaceutical structures were elucidated and registered for each group. The functional groups were divided into five distinct groups in drug design, and a correlation between identified functional group to pharmaceutical structure were indicated according to the classified functional groups of small molecule and drug categories; then defined their frequency in categories, at high abundant functional group present in categories reported. The most frequent rings were benzene and cyclohexane; the common acid functionality had been acetate (carboxy-); three most repeated saturated heterocyles are piperidine, piperazine and azetidine; among the unsaturated heterocyles, pyridine, imidazole and indole are noticed; This database, that may be guidance for researchers with the aim at designing new drugs.

Significant role of chemistry in drug development: a systematic journey from traditional to modern approaches with anti-HIV/AIDS drugs as examples

2021 ◽  
Vol 27 ◽  
Author(s):  
Madhu Yadav ◽  
Ritika Srivastava ◽  
Farha Naaz ◽  
Rajesh Verma ◽  
Ramendra K. Singh
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Development Process ◽  
New Drugs ◽  
Computer Assisted ◽  
Synthetic Chemistry ◽  
Drug Development Process ◽  
Drug Molecules ◽  
Hiv Aids

Background: Traditionally, various plant extracts having interesting biological properties were the main source of new drugs. In the last 30 years, the role of chemistry in combination with new technologies, like various computational techniques in chemistry, has witnessed a major upsurge in drug discovery and targeted drug delivery. Objective: This article provides a succinct overview of recent techniques of chemistry that have a great impact on the drug development process in general and also against HIV/AIDS. It focuses on new methods employed for drug development with an emphasis on in silico studies, including identifying drug targets, especially the proteins associated with specific diseases. Methods: The rational drug development process starts with the identification of a drug target as the first phase, which helps in the computer-assisted design of new drug molecules. Synthetic chemistry has a major impact on the drug development process because it provides new molecules for future study. Natural products based semisynthesis or microwave assisted synthesis is also involved in developing newly designed drug molecules. Further, the role of analytical chemistry involves extraction, fractionation, isolation and characterization of newly synthesized molecules. Results: Chemistry plays a key role in drug discovery and delivery by natural process or with the help of synthetic nanoparticles or nanomedicines. So, nanochemistry is also deeply involved in the development of new drugs and their applications. Conclusion: The previous era of drug discovery was dominated only by chemistry, but the modern approaches involve a comprehensive knowledge of synthetic chemistry, medicinal chemistry, computational chemistry and the concerned biological phenomenon.

Computational and Experimental Binding Mechanism of DNA-drug Interactions

2019 ◽  
Vol 24 (32) ◽  
pp. 3739-3757 ◽  
Author(s):  
Chandrabose Selvaraj ◽  
Sanjeev K. Singh
Keyword(s):  
Small Molecules ◽  
Self Assembly ◽  
Genetic Material ◽  
Dna Interaction ◽  
Significant Feature ◽  
Drug Molecules ◽  
Potential Applications ◽  
Novel Drug ◽  
Groove Binders ◽  
Molecular Docking And Dynamics

Nucleic acid is the key unit and a predominant genetic material for interpreting the fundamental basis of genetic information in an organism and now it is used for the evolution of a novel group of therapeutics. To identify the potential impact on the biological science, it receives high recognition in therapeutic applications. Due to its selective recognition of molecular targets and pathways, DNA significantly imparts tremendous specificity of action. Examining the properties of DNA holds numerous advantages in assembly, interconnects, computational elements, along with potential applications of DNA self-assembly and scaffolding include nanoelectronics, biosensors, and programmable/autonomous molecular machines. The interaction of low molecular weight, small molecules with DNA is a significant feature in pharmacology. Based on the mode of binding mechanisms, small molecules are categorized as intercalators and groove binders having a significant role in target-based drug development. The understanding mechanism of drug-DNA interaction plays an important role in the development of novel drug molecules with more effective and lesser side effects. This article attempts to outline those interactions of drug-DNA with both experimental and computational advances, including ultraviolet (UV) -visible spectroscopy, fluorescent spectroscopy, circular dichroism, nuclear magnetic resonance (NMR), molecular docking and dynamics, and quantum mechanical applications.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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