Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect

2021 ◽  
Vol 11 (1) ◽  
pp. 204-219
Author(s):  
Nahid Abbas ◽  
Mohammad Yusuf ◽  
Naseem Akhtar ◽  
Riaz A. Khan
Keyword(s):  
Drug Target ◽  
Architectural Design ◽  
Immunological Response ◽  
Structural Features ◽  
Stem Cell Technology ◽  
Drug Candidates ◽  
Current Perspective ◽  
Integrin Antagonists ◽  
Integrin Ligands ◽  
Drug Leads

Abstract The integrins belong to the cell-surface polypeptide family and are the mediating partners among the cells, and extracellular matrix (ECM). They are also involved in the biological processes of cell migration, wound healing, blood clotting, immunological response generation, tissue morphogenesis, leucocyte reticulations, and angiogenesis and are therefore very relevant in stem cell technology and are useful as biomarkers, diagnostic probes, and drug-target ligands. The ανβ3 (alpha-nu-beta3) integrin antagonists are an excellent target example for designing and developing newer drug candidates, drug leads and templates for various diseases, and physiological malfunctioning, including cancers. The current review examines the ανβ3 integrin structural features involved in the drug design and its antagonistic ligands and highlights the development of anti-ανβ3 integrin-antagonists as nano-architectural design-based nanomedicine, especially for cancer chemotherapy. The perspectival review discusses the ανβ3 integrin structure, mode of action, involved pathways, and the concepts utilized in nanomedicine design, and ligands related to integrins. It also covers the latest thyrointegrin approaches toward the development of anti-angiogenesis agents and entails the anti-angiogenesis approach to cancer growth inhibition through targeting by the anti-integrin ligands and related chemical entities. The current perspective on the nano-architectural design approach for the known anti-integrin compounds is also outlined.

Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

2019 ◽  
Vol 25 (25) ◽  
pp. 2772-2787 ◽  
Author(s):  
Raghu P. Mailavaram ◽  
Omar H.A. Al-Attraqchi ◽  
Supratik Kar ◽  
Shinjita Ghosh
Keyword(s):  
Drug Target ◽  
Therapeutic Agents ◽  
G Protein Coupled Receptors ◽  
Current Status ◽  
Renal Diseases ◽  
Adenosine A3 Receptor ◽  
Drug Candidates ◽  
Novel Drugs ◽  
The Family ◽  
G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

scholarly journals Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pusheng Quan ◽  
Kai Wang ◽  
Shi Yan ◽  
Shirong Wen ◽  
Chengqun Wei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Target ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Control Group ◽  
Drug Candidates ◽  
Novel Drug

AbstractThis study aimed to identify potential novel drug candidates and targets for Parkinson’s disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

scholarly journals The dimer-monomer equilibrium of SARS-CoV-2 main protease is affected by small molecule inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lucia Silvestrini ◽  
Norhan Belhaj ◽  
Lucia Comez ◽  
Yuri Gerelli ◽  
Antonino Lauria ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Dissociation Constant ◽  
Molecular Mechanisms ◽  
Antiviral Drug ◽  
Structural Features ◽  
Experimental Information ◽  
Detailed Knowledge ◽  
Main Protease ◽  
Equilibrium Dissociation ◽  
Drug Leads

AbstractThe maturation of coronavirus SARS-CoV-2, which is the etiological agent at the origin of the COVID-19 pandemic, requires a main protease Mpro to cleave the virus-encoded polyproteins. Despite a wealth of experimental information already available, there is wide disagreement about the Mpro monomer-dimer equilibrium dissociation constant. Since the functional unit of Mpro is a homodimer, the detailed knowledge of the thermodynamics of this equilibrium is a key piece of information for possible therapeutic intervention, with small molecules interfering with dimerization being potential broad-spectrum antiviral drug leads. In the present study, we exploit Small Angle X-ray Scattering (SAXS) to investigate the structural features of SARS-CoV-2 Mpro in solution as a function of protein concentration and temperature. A detailed thermodynamic picture of the monomer-dimer equilibrium is derived, together with the temperature-dependent value of the dissociation constant. SAXS is also used to study how the Mpro dissociation process is affected by small inhibitors selected by virtual screening. We find that these inhibitors affect dimerization and enzymatic activity to a different extent and sometimes in an opposite way, likely due to the different molecular mechanisms underlying the two processes. The Mpro residues that emerge as key to optimize both dissociation and enzymatic activity inhibition are discussed.

scholarly journals Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

2021 ◽  
Author(s):  
Julianne Tieu ◽  
Siddhee Sahasrabudhe ◽  
Paul Orchard ◽  
James Cloyd ◽  
Reena Kartha
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Candidates ◽  
Target Patient Population ◽  
Site Of Action ◽  
Repurposed Drugs ◽  
Gait Disturbances ◽  
Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

scholarly journals A Program for Automated Data Mining of PubChem to Screen a Billion Compounds and Generate by Machine Learning Based AutoQSAR Algorithm Anti-Corona Viral Drug Leads (Replicase Polyprotein 1ab Inhibitors) and in Silico Study of the Top Drug Lead Compounds

2020 ◽  
Author(s):  
Ben Geoffrey A S ◽  
Akhil Sanker ◽  
Host Antony Davidd ◽  
Judith Gracia
Keyword(s):  
Machine Learning ◽  
Data Mining ◽  
In Silico ◽  
Drug Target ◽  
Data Set ◽  
Lead Compounds ◽  
Pubchem Database ◽  
Drug Lead ◽  
Lead Generation ◽  
Drug Leads

Our work is composed of a python program for automatic data mining of PubChem database to collect data associated with the corona virus drug target replicase polyprotein 1ab (UniProt identifier : POC6X7 ) of data set involving active compounds, their activity value (IC50) and their chemical/molecular descriptors to run a machine learning based AutoQSAR algorithm on the data set to generate anti-corona viral drug leads. The machine learning based AutoQSAR algorithm involves feature selection, QSAR modelling, validation and prediction. The drug leads generated each time the program is run is reflective of the constantly growing PubChem database is an important dynamic feature of the program which facilitates fast and dynamic anti-corona viral drug lead generation reflective of the constantly growing PubChem database. The program prints out the top anti-corona viral drug leads after screening PubChem library which is over a billion compounds. The interaction of top drug lead compounds generated by the program and two corona viral drug target proteins, 3-Cystiene like Protease (3CLPro) and Papain like protease (PLpro) was studied and analysed using molecular docking tools. The compounds generated as drug leads by the program showed favourable interaction with the drug target proteins and thus we recommend the program for use in anti-corona viral compound drug lead generation as it helps reduce the complexity of virtual screening and ushers in an age of automatic ease in drug lead generation. The leads generated by the program can further be tested for drug potential through further In Silico, In Vitro and In Vivo testing <div><br></div><div><div>The program is hosted, maintained and supported at the GitHub repository link given below</div><div><br></div><div>https://github.com/bengeof/Drug-Discovery-P0C6X7</div></div><div><br></div>

scholarly journals Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wayne Vuong ◽  
Muhammad Bashir Khan ◽  
Conrad Fischer ◽  
Elena Arutyunova ◽  
Tess Lamer ◽  
...  
Keyword(s):  
Drug Target ◽  
Covalent Modification ◽  
Human Coronavirus ◽  
Feline Infectious Peritonitis ◽  
Drug Candidates ◽  
Main Protease ◽  
Coronavirus Infection ◽  
Reversible Formation ◽  
Nanomolar Range ◽  
Feline Coronavirus

Abstract The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.

scholarly journals Drug Target Exploitable Structural Features of Adenylyl Cyclase Activity inSchistosoma mansoni

2012 ◽  
Vol 6 ◽  
pp. DTI.S10219 ◽  
Author(s):  
Andreas N. Mbah ◽  
Henri L. Kamga ◽  
Omotayo R. Awofolu ◽  
Raphael D. Isokpehi
Keyword(s):  
Adenylyl Cyclase ◽  
Drug Target ◽  
Structural Features ◽  
Cyclase Activity ◽  
Adenylyl Cyclase Activity

Predictive Human Intestinal Absorption QSAR Models Using Bayesian Regularized Neural Networks

2005 ◽  
Vol 58 (12) ◽  
pp. 859 ◽  
Author(s):  
Mitchell J. Polley ◽  
Frank R. Burden ◽  
David A. Winkler
Keyword(s):  
Intestinal Absorption ◽  
Experimental Error ◽  
Dosage Form ◽  
Molecular Descriptors ◽  
Oral Dosage ◽  
Health Costs ◽  
Late Development ◽  
Drug Candidates ◽  
Qsar Models ◽  
Drug Leads

An oral dosage form is generally the most popular with patients. Many drug candidates fail in late development because of unfavourable absorption and pharmacokinetic profiles, or toxicity, among other factors (ADMET properties). This contributes to the fall in the efficiency of the pharmaceutical industry and to the rise in health costs. The ability to predict ADMET properties of drug leads can contribute to overcoming this problem. We have modelled intestinal absorption using several types of molecular descriptors and a non-linear Bayesian regularized neural network. Our models show very good predictive properties and are able to account for essentially all of the variance in the data that is not due to experimental error.

scholarly journals Engineering of Marine-derived Antimicrobial Peptides (mAMPs) into Improved Anti-infective Drug Leads: A Mini-review

2021 ◽  
Vol 1192 (1) ◽  
pp. 012013
Author(s):  
L Sukmarini
Keyword(s):  
Antimicrobial Peptides ◽  
Chemical Diversity ◽  
Cytotoxic Activities ◽  
Small Molecular Weight ◽  
Resistance Development ◽  
Drug Candidates ◽  
Bacteria And Fungi ◽  
Drug Leads ◽  
Net Positive Charge

Abstract Marine-derived antimicrobial compounds possess chemical diversity varying from peptides, fatty acids to terpenes, alkaloids, and polyketides. These compounds, especially of peptide origin called antimicrobial peptides (AMPs), are present in the majority of marine organisms, including microbes (bacteria and fungi), invertebrates (molluscs, echinoderms, and sponges), vertebrates (fish and mammals), and plants (marine algae). They are defined by small molecular weight (less than 10 kDa), a net positive charge, and amphipathic structures. Moreover, due to their profound in vitro antimicrobial and cytotoxic activities and a low risk for resistance development, naturally occurring marine-derived AMPs (mAMPs) have been used as drug design templates for a large variety of semi-synthetic or synthetic AMPs, some of which have reached clinical trials. This mini-review aims to discuss AMPs from marine sources, mainly emphasizing the engineering of these peptides with improved pharmacological properties to develop drug candidates. Some selected recent examples of these engineered mAMPs as anti-infective drug leads are herein highlighted.

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