Chagas Disease Treatment and Rational Drug Discovery: A Challenge That Remains

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

Download Full-text

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

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.

Download Full-text

Rational Drug Discovery of HCV Helicase Inhibitor: Improved Docking Accuracy with Multiple Seeding in AutoDock Vina and In Si tu Minimization

Current Computer - Aided Drug Design ◽

10.2174/1573409912666161130122622 ◽

2017 ◽

Vol 13 (2) ◽

pp. 160-169 ◽

Cited By ~ 5

Author(s):

See K. Lim ◽

Rozana Othman ◽

Rohana Yusof ◽

Choon H. Heh

Keyword(s):

Drug Discovery ◽

Autodock Vina ◽

Rational Drug ◽

Docking Accuracy

Download Full-text

Design and synthesis of mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113646 ◽

2021 ◽

pp. 113646

Author(s):

Iván Beltran-Hortelano ◽

Richard L. Atherton ◽

Mercedes Rubio-Hernández ◽

Julen Sanz-Serrano ◽

Verónica Alcolea ◽

...

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Mannich Base ◽

Design And Synthesis ◽

Lead Compounds

Download Full-text

Innovations and Implementations of Computer Aided Drug Discovery Strategies in Rational Drug Design

10.1007/978-981-15-8936-2 ◽

2021 ◽

Keyword(s):

Drug Discovery ◽

Drug Design ◽

Rational Drug Design ◽

Rational Drug ◽

Computer Aided

Download Full-text

Nuclear hormone receptors and rational drug discovery

Biochemical Society Transactions ◽

10.1042/bst0190894 ◽

1991 ◽

Vol 19 (4) ◽

pp. 894-897

Author(s):

Stephen Green

Keyword(s):

Drug Discovery ◽

Hormone Receptors ◽

Nuclear Hormone Receptors ◽

Rational Drug

Download Full-text

Screening of phytochemicals from Curcuma longa for their inhibitory activity on SARS-CoV-2: An in-silico study

Anti-Infective Agents ◽

10.2174/2211352519666210719090130 ◽

2021 ◽

Vol 19 ◽

Author(s):

Preeya Negi ◽

Lalita Das ◽

Surya Prakash ◽

Vaishali M. Patil

Keyword(s):

Drug Discovery ◽

In Silico ◽

Curcuma Longa ◽

Docking Studies ◽

Primary Objective ◽

In Silico Screening ◽

Rational Drug ◽

In Silico Study ◽

Speed Up ◽

Novel Coronavirus

Introduction: Natural products or phytochemicals have always been useful as effective therapeutics and for providing the lead for rational drug discovery approaches specific to anti-viral therapeutics. Methods: The ongoing pandemic caused by novel coronavirus has created a demand for effective therapeutics. Thus, to achieve the primary objective to search for effective anti-viral therapeutics, in silico screening of phytochemicals present in Curcuma longa extract (ex. Curcumin) has been planned. Results: The present work involves the evaluation of ADME properties and molecular docking studies. Conclusion: The application of rationalized drug discovery approaches to screen the diverse natural resources will speed up the anti-COVID drug discovery efforts and benefit the global community.

Download Full-text

Perspective: The promises of a holistic view of proteins—impact on antibody engineering and drug discovery

Bioscience Reports ◽

10.1042/bsr20181958 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 12

Author(s):

Ser-Xian Phua ◽

Kwok-Fong Chan ◽

Chinh Tran-To Su ◽

Jun-Jie Poh ◽

Samuel Ken-En Gan

Keyword(s):

Drug Discovery ◽

Drug Design ◽

Antibody Engineering ◽

Rational Drug Design ◽

Biomedical Science ◽

Great Promise ◽

Holistic View ◽

Rational Drug ◽

Big Picture ◽

Reductionist Approach

AbstractThe reductionist approach is prevalent in biomedical science. However, increasing evidence now shows that biological systems cannot be simply considered as the sum of its parts. With experimental, technological, and computational advances, we can now do more than view parts in isolation, thus we propose that an increasing holistic view (where a protein is investigated as much as a whole as possible) is now timely. To further advocate this, we review and discuss several studies and applications involving allostery, where distant protein regions can cross-talk to influence functionality. Therefore, we believe that an increasing big picture approach holds great promise, particularly in the areas of antibody engineering and drug discovery in rational drug design.

Download Full-text