scholarly journals An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets

2020 ◽  
Author(s):  
Brian Olson ◽  
Anthony Cruz ◽  
Lieyang Chen ◽  
Mossa Ghattas ◽  
Yeonji Ji ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Effective Vaccine ◽  
Mapping Data ◽  
Site Analysis ◽  
Small Molecule Drug ◽  
Small Molecule Drugs ◽  
Resultant Data ◽  
Severity Of The Disease ◽  
Solvation Theory

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets. Grid Inhomogeneous Solvation Theory maps were generated using AmberTools cpptraj-GIST and Hydration Site Analysis maps were created using SSTmap code. The resultant data can be applied to drug design efforts: scoring solvent displacement for docking, rational lead modification, prioritization of ligand- and protein- based pharmacophore elements, and creation of water-based pharmacophores. Herein, we demonstrate the use of the solvation thermodynamic mapping data. It is hoped that this freely provided data will aid in small molecule drug discovery efforts to defeat SARS-CoV-2.

scholarly journals An Online Repository of Solvation Thermodynamic and Structural Maps of SARS-CoV-2 Targets

2020 ◽  
Author(s):  
Brian Olson ◽  
Anthony Cruz ◽  
Lieyang Chen ◽  
Mossa Ghattas ◽  
Yeonji Ji ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Effective Vaccine ◽  
Mapping Data ◽  
Site Analysis ◽  
Small Molecule Drug ◽  
Small Molecule Drugs ◽  
Resultant Data ◽  
Severity Of The Disease ◽  
Solvation Theory

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets. Grid Inhomogeneous Solvation Theory maps were generated using AmberTools cpptraj-GIST and Hydration Site Analysis maps were created using SSTmap code. The resultant data can be applied to drug design efforts: scoring solvent displacement for docking, rational lead modification, prioritization of ligand- and protein- based pharmacophore elements, and creation of water-based pharmacophores. Herein, we demonstrate the use of the solvation thermodynamic mapping data. It is hoped that this freely provided data will aid in small molecule drug discovery efforts to defeat SARS-CoV-2.

Application of Biological Target Fishing Technology in Drug Discovery

2020 ◽  
Vol 980 ◽  
pp. 210-219
Author(s):  
Xian Zhi Ye
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Drug Targets ◽  
Surface Plasma Resonance ◽  
Practical Applications ◽  
Small Molecule Drug ◽  
New Methods ◽  
Small Molecule Drugs ◽  
Biological Target ◽  
Target Fishing

Target fishing, a cutting-edge technology for drug research and development, plays a significant role in drug discovery. Varieties of methods for finding small-molecule drug targets have come into being driven by genomics, proteomics, bioinformatics and other technologies. These new methods are mainly based on the expression of gene or protein and proteins properties, including affinity and stability and so on. A serious challenge for the most widely used small molecule drugs is the discovery and identification of biological (and potential therapeutic) targets. Herein, we enumerate five biological target fishing techniques, including surface plasma resonance (SPR) techniques, random photo modified probes, drug affinity responsive target stability, fishing-rod strategy, and photo affinity labeling. And then we introduces the principles of operation, practical applications in the biological field of five methods, and analysis of their shortcomings.

meta-Non-flat substituents: a novel molecular design to improve aqueous solubility in small molecule drug discovery

2021 ◽  
Author(s):  
Yuki Ichikawa ◽  
Michiaki Hiramatsu ◽  
Yusuke Mita ◽  
Makoto Makishima ◽  
Yotaro Matsumoto ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Molecular Design ◽  
Aqueous Solubility ◽  
Small Molecule Drug ◽  
Small Molecule Drugs

We found a novel molecular design for improvement in the aqueous solubility of small molecule drugs.

scholarly journals Elucidation of DNA Repair Function of PfBlm and Potentiation of Artemisinin Action by a Small-Molecule Inhibitor of RecQ Helicase

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Niranjan Suthram ◽  
Siladitya Padhi ◽  
Payal Jha ◽  
Sunanda Bhattacharyya ◽  
Gopalakrishnan Bulusu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Small Molecule ◽  
Economic Burden ◽  
Drug Targets ◽  
Small Molecule Inhibitor ◽  
Morbidity And Mortality ◽  
Effective Vaccine ◽  
Recq Helicase ◽  
Molecule Inhibitor

Malaria continues to be a serious threat to humankind not only because of the morbidity and mortality associated with the disease but also due to the huge economic burden that it imparts. Resistance to all available drugs and the unavailability of an effective vaccine cry for an urgent discovery of newer drug targets.

scholarly journals Host Directed Therapies for Tuberculous Meningitis

2020 ◽  
Vol 5 ◽  
pp. 292
Author(s):  
Angharad G Davis ◽  
Joseph Donovan ◽  
Marise Bremer ◽  
Ronald Van Toorn ◽  
Johan Schoeman ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Outcomes ◽  
Small Molecule ◽  
Tuberculous Meningitis ◽  
Drug Targets ◽  
Immunomodulatory Drugs ◽  
Small Molecule Drug ◽  
New Knowledge ◽  
Repurposed Drugs ◽  
Proven Benefit

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

Strategies to identify ligands for orphan G-protein-coupled receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 789-793 ◽  
Author(s):  
G. Milligan
Keyword(s):  
Drug Design ◽  
G Protein ◽  
Small Molecule ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Protein Targets ◽  
Small Molecule Drug ◽  
Natural Ligands ◽  
G Protein Coupled

G-protein-coupled receptors are the most tractable class of protein targets for small molecule drug design. Sequencing of the human genome allied to bio-informatic analysis has identified a large number of putative receptors for which the natural ligands remain undefined. A range of currently employed and developing strategies to identify ligands that interact with these orphan receptors and to validate them as drug targets are described and discussed.

Small molecule drug conjugates (SMDCs): an emerging strategy for anticancer drug design and discovery

2021 ◽  
Vol 45 (12) ◽  
pp. 5291-5321
Author(s):  
Tarun Kumar Patel ◽  
Nilanjan Adhikari ◽  
Sk. Abdul Amin ◽  
Swati Biswas ◽  
Tarun Jha ◽  
...  
Keyword(s):  
Drug Design ◽  
Anticancer Drug ◽  
Small Molecule ◽  
Chemotherapeutic Agents ◽  
Drug Molecule ◽  
Lysosomal Ph ◽  
Small Molecule Drug ◽  
Drug Conjugates ◽  
Small Molecule Drugs ◽  
Tumor Environment

Mechanisms of how SMDCs work. Small molecule drugs are conjugated with the targeted ligand using pH sensitive linkers which allow the drug molecule to get released at lower lysosomal pH. It helps to accumulate the chemotherapeutic agents to be localized in the tumor environment upon cleaving of the pH-labile bonds.

scholarly journals PolypharmDB, a Deep Learning-Based Resource, Quickly Identifies Repurposed Drug Candidates for COVID-19

2020 ◽  
Author(s):  
Dar'ya S. Redka ◽  
Stephen S. MacKinnon ◽  
Melissa Landon ◽  
Andreas Windemuth ◽  
Naheed Kurji ◽  
...  
Keyword(s):  
Deep Learning ◽  
Small Molecule ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Therapeutic Interventions ◽  
Clinical Environment ◽  
Drug Candidates ◽  
Small Molecule Drugs

<p>There is an immediate need to discover treatments for COVID-19, the pandemic caused by the SARS-CoV-2 virus. Standard small molecule drug discovery workflows that start with library screens are an impractical path forward given the timelines to discover, develop, and test clinically. To accelerate the time to patient testing, here we explored the therapeutic potential of small molecule drugs that have been tested to some degree in a clinical environment, including approved medications, as possible therapeutic interventions for COVID-19. Motivating our process is a concept termed polypharmacology, i.e. off-target interactions that may hold therapeutic potential. In this work, we used Ligand Design, our deep learning drug design platform, to interrogate the polypharmacological profiles of an internal collection of small molecule drugs with federal approval or going through clinical trials, with the goal of identifying molecules predicted to modulate targets relevant for COVID-19 treatment. Resulting from our efforts is PolypharmDB, a resource of drugs and their predicted binding of protein targets across the human proteome. Mining PolypharmDB yielded molecules predicted to interact with human and viral drug targets for COVID-19, including host proteins linked to viral entry and proliferation and key viral proteins associated with the virus life-cycle. Further, we assembled a collection of prioritized approved drugs for two specific host-targets, TMPRSS2 and cathepsin B, whose joint inhibition was recently shown to block SARS-CoV-2 virus entry into host cells. Overall, we demonstrate that our approach facilitates rapid response, identifying 30 prioritized candidates for testing for their possible use as anti-COVID drugs. Using the PolypharmDB resource, it is possible to identify repurposed drug candidates for newly discovered targets within a single work day. We are making a complete list of the molecules we identified available at no cost to partners with the ability to test them for efficacy, in vitro and/or clinically.</p><div><br></div>

scholarly journals Host Directed Therapies for Tuberculous Meningitis

2021 ◽  
Vol 5 ◽  
pp. 292
Author(s):  
Angharad G. Davis ◽  
Joseph Donovan ◽  
Marise Bremer ◽  
Ronald Van Toorn ◽  
Johan Schoeman ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Outcomes ◽  
Small Molecule ◽  
Tuberculous Meningitis ◽  
Drug Targets ◽  
Immunomodulatory Drugs ◽  
Small Molecule Drug ◽  
New Knowledge ◽  
Repurposed Drugs ◽  
Proven Benefit

A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.

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