scholarly journals A machine learning and network framework to discover new indications for small molecules

2019 ◽  
Author(s):  
Coryandar Gilvary ◽  
Jamal Elkhader ◽  
Neel Madhukar ◽  
Claire Henchcliffe ◽  
Marcus D. Goncalves ◽  
...  
Keyword(s):  
Drug Development ◽  
Small Molecules ◽  
Kinase Inhibitor ◽  
Drug Repurposing ◽  
Chemical Information ◽  
Respiratory Illnesses ◽  
Drug Classes ◽  
Future Drug ◽  
Drug Similarity

AbstractDrug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson’s disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

Positron Emission Tomography for Future Drug Development

2011 ◽  
Vol 1 (2) ◽  
pp. 137-151
Author(s):  
Ryogo Minamimoto ◽  
Chumpol Theeraladanon ◽  
Akiko Suzuki ◽  
Tomio Inoue
Keyword(s):  
Positron Emission Tomography ◽  
Drug Development ◽  
Emission Tomography ◽  
Positron Emission ◽  
Future Drug

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii419-iii419
Author(s):  
Sheetal Phadnis ◽  
Mari Hagiwara ◽  
Anna Yaffe ◽  
Carole Mitchell ◽  
Theodore Nicolaides ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas ◽  
Volumetric Response

Abstract INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

scholarly journals Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

2020 ◽  
Author(s):  
Meenakshisundaram Balasubramaniam ◽  
Robert Shmookler Reis
Keyword(s):  
Small Molecules ◽  
Drug Targeting ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Hiv Treatment ◽  
Investigational Drug ◽  
Docking Simulations ◽  
Investigational Drugs ◽  
Low Toxicity

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.

scholarly journals Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase

2020 ◽  
Author(s):  
Christian Seitz ◽  
Lorenzo Casalino ◽  
Robert Konecny ◽  
Gary Huber ◽  
Rommie E. Amaro ◽  
...  
Keyword(s):  
Drug Development ◽  
Ligand Binding ◽  
Binding Site ◽  
Brownian Dynamics ◽  
Drug Binding ◽  
Binding Mechanism ◽  
Drug Effectiveness ◽  
Future Drug ◽  
Dynamics Simulations ◽  
Inhibit Antibody

AbstractInfluenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase.Statement of SignificanceThe influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.

scholarly journals Pharmacological therapy and cardiovascular risk reduction for type 2 diabetes

2020 ◽  
Vol 66 (9) ◽  
pp. 1283-1288
Author(s):  
Eduardo Bello Martins ◽  
Eduardo Gomes Lima ◽  
Fábio Grunspun Pitta ◽  
Leticia Neves Solon Carvalho ◽  
Thiago Dias de Queiroz ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
Pharmacological Therapy ◽  
High Cardiovascular Risk ◽  
Cardiovascular Risk Reduction ◽  
Drug Classes ◽  
Clinical Benefits

SUMMARY The pharmacological therapy for type 2 diabetes mellitus has presented important advances in recent years, which has impacted the treatment of patients with established cardiovascular disease or with high cardiovascular risk. In this scenario, two drug classes have emerged and demonstrated clear clinical benefits: SGLT-2 inhibitors and GLP-1 agonists. The present review discusses the pharmacology, adverse effects, and clinical trials that have demonstrated the benefits of these medications in reducing cardiovascular risk.

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