scholarly journals Chalcones as a basis for computer-aided drug design: innovative approaches to tackle malaria

2019 ◽  
Vol 11 (20) ◽  
pp. 2635-2646 ◽  
Author(s):  
Marilia NN Lima ◽  
Bruno J Neves ◽  
Gustavo C Cassiano ◽  
Marcelo N Gomes ◽  
Kaira CP Tomaz ◽  
...  
Keyword(s):  
Drug Design ◽  
Plasmodium Berghei ◽  
Experimental Validation ◽  
Docking Studies ◽  
Antiplasmodial Activity ◽  
Computer Aided Drug Design ◽  
Protein Targets ◽  
Computer Aided ◽  
Falciparum Protein

Aim: Computer-aided drug design approaches were applied to identify chalcones with antiplasmodial activity. Methodology: The virtual screening was performed as follows: structural standardization of in-house database of chalcones; identification of potential Plasmodium falciparum protein targets for the chalcones; homology modeling of the predicted P. falciparum targets; molecular docking studies; and in vitro experimental validation. Results: Using these models, we prioritized 16 chalcones with potential antiplasmodial activity, for further experimental evaluation. Among them, LabMol-86 and LabMol-87 showed potent in vitro antiplasmodial activity against P. falciparum, while LabMol-63 and LabMol-73 were potent inhibitors of Plasmodium berghei progression into mosquito stages. Conclusion: Our results encourage the exploration of chalcones in hit-to-lead optimization studies for tackling malaria.

scholarly journals Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

2021 ◽  
Vol 22 (9) ◽  
pp. 4688
Author(s):  
Mootaz M. Salman ◽  
Zaid Al-Obaidi ◽  
Philip Kitchen ◽  
Andrea Loreto ◽  
Roslyn M. Bill ◽  
...  
Keyword(s):  
Drug Design ◽  
Neurodegenerative Diseases ◽  
Docking Studies ◽  
New Drugs ◽  
Computer Aided Drug Design ◽  
Biological Assays ◽  
Advantages And Disadvantages ◽  
Computer Aided ◽  
Research Challenge ◽  
The Cost

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.

scholarly journals Discovery and evaluation of entry inhibitors for SARS-CoV-2 and its emerging variants

2021 ◽  
Author(s):  
Arpan Acharya ◽  
Kabita Pandey ◽  
Michellie Thurman ◽  
Elizabeth Klug ◽  
Jay Trivedi ◽  
...  
Keyword(s):  
Drug Design ◽  
Antiviral Activity ◽  
Binding Mode ◽  
Spike Glycoprotein ◽  
Computer Aided Drug Design ◽  
Entry Inhibitors ◽  
Computer Aided ◽  
Novel Coronavirus ◽  
Potential Inhibitors

The outbreak of SARS-CoV-2 is responsible for the COVID-19 pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design (CADD) approach, we identified and validated 5 potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both the compounds showed antiviral activity with IC 50 values in the micromolar range (MU-UNMC-1: IC 50 = 0.67 μM and MU-UNMC-2: IC 50 = 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC 50 = 9.27 μM & 3.00 μM) and Scotland variant B.1.222 (IC 50 = 2.64 μM & 1.39 μM) respectively. Following these assays, we conducted ‘induced-fit (flexible) docking’ to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir (RDV), the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2 specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir, suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19, infected individuals.

Computer-Aided Drug Design Applied to Secondary Metabolites as Anticancer Agents

2020 ◽  
Vol 20 (19) ◽  
pp. 1677-1703
Author(s):  
Rodrigo Santos Aquino de Araújo ◽  
Edeildo Ferreira da Silva-Junior ◽  
Thiago Mendonça de Aquino ◽  
Marcus Tullius Scotti ◽  
Hamilton M. Ishiki ◽  
...  
Keyword(s):  
Drug Design ◽  
Anticancer Agents ◽  
Cost Reduction ◽  
Computer Aided Drug Design ◽  
Structure Based Drug Design ◽  
Chemical Structures ◽  
Computer Aided ◽  
Low Costs ◽  
New Compounds

: Computer-Aided Drug Design (CADD) techniques have garnered a great deal of attention in academia and industry because of their great versatility, low costs, possibilities of cost reduction in in vitro screening and in the development of synthetic steps; these techniques are compared with highthroughput screening, in particular for candidate drugs. The secondary metabolism of plants and other organisms provide substantial amounts of new chemical structures, many of which have numerous biological and pharmacological properties for virtually every existing disease, including cancer. In oncology, compounds such as vimblastine, vincristine, taxol, podophyllotoxin, captothecin and cytarabine are examples of how important natural products enhance the cancer-fighting therapeutic arsenal. : In this context, this review presents an update of Ligand-Based Drug Design and Structure-Based Drug Design techniques applied to flavonoids, alkaloids and coumarins in the search of new compounds or fragments that can be used in oncology. : A systematical search using various databases was performed. The search was limited to articles published in the last 10 years. : The great diversity of chemical structures (coumarin, flavonoids and alkaloids) with cancer properties, associated with infinite synthetic possibilities for obtaining analogous compounds, creates a huge chemical environment with potential to be explored, and creates a major difficulty, for screening studies to select compounds with more promising activity for a selected target. CADD techniques appear to be the least expensive and most efficient alternatives to perform virtual screening studies, aiming to selected compounds with better activity profiles and better “drugability”.

Computer Aided Drug Design Approaches for Identification of Novel Autotaxin (ATX) Inhibitors

2016 ◽  
Vol 23 (17) ◽  
pp. 1708-1724 ◽  
Author(s):  
Eleni Vrontaki ◽  
Georgia Melagraki ◽  
Eleanna Kaffe ◽  
Thomas Mavromoustakos ◽  
George Kokotos ◽  
...  
Keyword(s):  
Drug Design ◽  
Computer Aided Drug Design ◽  
Computer Aided

Prospects for Discovering the Secondary Metabolites of Cordyceps Sensu Lato by the Integrated Strategy

2020 ◽  
Vol 17 (2) ◽  
pp. 97-120
Author(s):  
Shabana Bibi ◽  
Yuan-Bing Wang ◽  
De-Xiang Tang ◽  
Mohammad Amjad Kamal ◽  
Hong Yu
Keyword(s):  
Drug Design ◽  
Biological Activities ◽  
Design Methods ◽  
Chinese Herbs ◽  
Active Metabolites ◽  
Computer Aided Drug Design ◽  
Design Concepts ◽  
Conventional Drug ◽  
Computer Aided ◽  
Design Techniques

: Some species of Cordyceps sensu lato are famous Chinese herbs with significant biological activities, often used as edible food and traditional medicine in China. Cordyceps represents the largest entomopathogenic group of fungi, including 40 genera and 1339 species in three families and incertae sedis of Hypocreales. Objective: Most of the Cordyceps-derivatives have been approved clinically for the treatment of various diseases such as diabetes, cancers, inflammation, cardiovascular, renal and neurological disorders and are used worldwide as supplements and herbal drugs, but there is still need for highly efficient Cordyceps-derived drugs for fatal diseases with approval of the U.S. Food and Drug Administration. Methods: Computer-aided drug design concepts could improve the discovery of putative Cordyceps- derived medicine within less time and low budget. The integration of computer-aided drug design methods with experimental validation has contributed to the successful discovery of novel drugs. Results: This review focused on modern taxonomy, active metabolites, and modern drug design techniques that could accelerate conventional drug design and discovery of Cordyceps s. l. Successful application of computer-aided drug design methods in Cordyceps research has been discussed. Conclusion: It has been concluded that computer-aided drug design techniques could influence the multiple target-focused drug design, because each metabolite of Cordyceps has shown significant activities for the various diseases with very few or no side effects.

Sign in / Sign up

Export Citation Format

Share Document