scholarly journals Pushing The Limits Of Detection Of Weak Binding Using Fragment Based Drug Discovery: Identification Of New Cyclophilin Binders

2017 ◽  
Author(s):  
Charis Georgiou ◽  
Iain W. McNae ◽  
Martin A. Wear ◽  
Harris Ioannidis ◽  
Julien Michel ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dissociation Constants ◽  
Md Simulations ◽  
Detailed Comparison ◽  
Protein Family ◽  
Computational Techniques ◽  
X Ray Diffraction ◽  
Drug Candidates ◽  
Weak Binding ◽  
Fragment Based Drug Discovery

Fragment Based Drug Discovery (FBDD) is an increasingly popular method to identify novel small-molecule drug candidates. One of the limitations of the approach is the difficulty of accurately characterizing weak binding events. This work reports a combination of X-ray diffraction, surface plasmon resonance (SPR) experiments and molecular dynamics (MD) simulations, for the characterisation of binders to different isoforms of the cyclophilin (Cyp) protein family. Although several Cyp inhibitors have been reported in the literature, it has proven challenging to achieve high binding selectivity for different isoforms of this protein family. The present studies have led to the identification of several structurally novel fragments that bind to diverse Cyp isoforms in distinct pockets with low millimolar dissociation constants. A detailed comparison of the merits and drawbacks of the experimental and computational techniques is presented, and emerging strategies for designing ligands with enhanced isoform specificity are described.

scholarly journals Fragment Library of Natural Products and Compound Databases for Drug Discovery

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1518 ◽  
Author(s):  
Ana L. Chávez-Hernández ◽  
Norberto Sánchez-Cruz ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Synthetic Compounds ◽  
Drug Candidates ◽  
Compound Libraries ◽  
Chemical Database ◽  
Fragment Library ◽  
Further Development ◽  
Fragment Libraries ◽  
Fragment Based Drug Discovery

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.

scholarly journals Pushing the Limits of Detection of Weak Binding Using Fragment-Based Drug Discovery: Identification of New Cyclophilin Binders

2017 ◽  
Vol 429 (16) ◽  
pp. 2556-2570 ◽  
Author(s):  
Charis Georgiou ◽  
Iain McNae ◽  
Martin Wear ◽  
Harris Ioannidis ◽  
Julien Michel ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Limits Of Detection ◽  
Weak Binding ◽  
Fragment Based Drug Discovery

scholarly journals Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 4016
Author(s):  
Blake Rushing ◽  
Denise Rohlik ◽  
Sourav Roy ◽  
D. Skaff ◽  
Brandon Garcia
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Dissociation Constants ◽  
Inflammatory Diseases ◽  
Alternative Pathway ◽  
Lectin Pathway ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Intervention Point ◽  
Fragment Based Drug Discovery

The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery approach using surface plasmon resonance (SPR) and molecular modeling to identify and characterize novel C1r-binding small-molecule fragments. SPR was used to screen a 2000-compound fragment library for binding to human C1r. This led to the identification of 24 compounds that bound C1r with equilibrium dissociation constants ranging between 160–1700 µM. Two fragments, termed CMP-1611 and CMP-1696, directly inhibited classical pathway-specific complement activation in a dose-dependent manner. CMP-1611 was selective for classical pathway inhibition, while CMP-1696 also blocked the lectin pathway but not the alternative pathway. Direct binding experiments mapped the CMP-1696 binding site to the serine protease domain of C1r and molecular docking and molecular dynamics studies, combined with C1r autoactivation assays, suggest that CMP-1696 binds within the C1r active site. The group of structurally distinct fragments identified here, along with the structure–activity relationship profiling of two lead fragments, form the basis for future development of novel high-affinity C1r-binding, classical pathway-specific, small-molecule complement inhibitors.

Application of Advanced Technologies in Natural Product Research: A Review with Special Emphasis on ADMET Profiling

2020 ◽  
Vol 21 (10) ◽  
pp. 751-767
Author(s):  
Pobitra Borah ◽  
Sangeeta Hazarika ◽  
Satyendra Deka ◽  
Katharigatta N. Venugopala ◽  
Anroop B. Nair ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Natural Product ◽  
Dynamic Range ◽  
Early Stage ◽  
Attrition Rate ◽  
Drug Candidates ◽  
Advanced Technologies ◽  
Natural Product Research ◽  
The Status ◽  
Safety Parameters

The successful conversion of natural products (NPs) into lead compounds and novel pharmacophores has emboldened the researchers to harness the drug discovery process with a lot more enthusiasm. However, forfeit of bioactive NPs resulting from an overabundance of metabolites and their wide dynamic range have created the bottleneck in NP researches. Similarly, the existence of multidimensional challenges, including the evaluation of pharmacokinetics, pharmacodynamics, and safety parameters, has been a concerning issue. Advancement of technology has brought the evolution of traditional natural product researches into the computer-based assessment exhibiting pretentious remarks about their efficiency in drug discovery. The early attention to the quality of the NPs may reduce the attrition rate of drug candidates by parallel assessment of ADMET profiling. This article reviews the status, challenges, opportunities, and integration of advanced technologies in natural product research. Indeed, emphasis will be laid on the current and futuristic direction towards the application of newer technologies in early-stage ADMET profiling of bioactive moieties from the natural sources. It can be expected that combinatorial approaches in ADMET profiling will fortify the natural product-based drug discovery in the near future.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Appraisal of the role of In silico Methods in Pyrazole based drug design

2020 ◽  
Vol 20 ◽  
Author(s):  
Smriti Sharma ◽  
Vinayak Bhatia
Keyword(s):  
Drug Design ◽  
In Silico ◽  
Md Simulations ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Computational Techniques ◽  
Neuroprotective Drugs ◽  
Pharmacological Potential ◽  
Available Information ◽  
Anti Fungal

: Pyrazole and its derivatives are a pharmacologically significant active scaffold that have innumerable physiological and pharmacological activities. They can be very good targets for the discovery of novel anti-bacterial, anticancer, anti-inflammatory, anti-fungal, anti-tubercular, antiviral, antioxidant, antidepressant, anti-convulsant and neuroprotective drugs. This review focuses on the importance of in silico manipulations of pyrazole and its derivatives for medicinal chemistry. The authors have discussed currently available information on the use of computational techniques like molecular docking, structure-based virtual screening (SBVS), molecular dynamics (MD) simulations, quantitative structure activity relationship (QSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to drug design using pyrazole moieties. Pyrazole based drug design is mainly dependent on the integration of experimental and computational approaches. The authors feel that more studies need to be done to fully explore the pharmacological potential of the pyrazole moiety and in silico method can be of great help.

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