Discovery of Octahydroisoindolone as a Scaffold for the Selective Inhibition of Chitinase B1 from Aspergillus fumigatus: In Silico Drug Design Studies

Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1–5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC50 prediction of our candidates (60–200 μM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.

Serratia marcescens secretes proteases and chitinases with larvicidal activity against Anopheles dirus

ABSTRACTVector control, the most efficient tool to reduce mosquito-borne disease transmission, has been compromised by the rise of insecticide resistance. Recent studies suggest the potential of mosquito-associated microbiota as a source for new biocontrol agents or new insecticidal chemotypes. In this study, we identified a strain of Serratia marcescens that has larvicidal activity against Anopheles dirus, an important malaria vector in Southeast Asia. This bacterium secretes heat-labile larvicidal macromolecules when cultured under static condition at 25°C but not 37°C. Two major protein bands of approximately 55 kDa and 110 kDa were present in spent medium cultured at 25°C but not at 37°C. The Liquid Chromatography-Mass Spectrometry (LC-MS) analyses of these two protein bands identified several proteases and chitinases that were previously reported for insecticidal properties against agricultural insect pests. The treatment with protease and chitinase inhibitors led to a reduction in larvicidal activity, confirming that these two groups of enzymes are responsible for the macromolecule’s toxicity. Taken together, our results suggest a potential use of these enzymes in the development of larvicidal agents against Anopheles mosquitoes.

Chitinases: Therapeutic Scaffolds for Allergy and Inflammation

Background: Chitinases are the evolutionary conserved glycosidic enzymes that are characterized by their ability to cleave the naturally abundant polysaccharide chitin. The potential role of chitinases has been identified in the manifestation of various allergies and inflammatory diseases. In recent years, chitinases inhibitors are emerging as an alluring area of interest for the researchers and scientists and there is a dire need for the development of potential and safe chitinase antagonists for the prophylaxis and treatment of several diseases. Objective: The present review expedites the role of chitinases and their inhibitors in inflammation and related disorders. Methods: At first, an exhaustive survey of literature and various patents available related to chitinases were carried out. Useful information on chitinases and their inhibitor was gathered from the authentic scientific databases namely SCOPUS, EMBASE, PUBMED, GOOGLE SCHOLAR, MEDLINE, EMBASE, EBSCO, WEB OF SCIENCE, etc. This information was further analyzed and compiled up to prepare the framework of the review article. The search strategy was conducted by using queries with key terms “ chitin”, “chitinase”, “chitotrisidase”, “acidic mammalian chitinase”, “chitinase inhibitors”, “asthma” and “chitinases associated inflammatory disorders”, etc. The patents were searched using the key terms “chitinases and uses thereof”, “chitinase inhibitors”, “chitin-chitinase associated pathological disorders” etc. from www.google.com/patents, www.freepatentsonline.com, and www.scopus.com. Results: The present review provides a vision for apprehending human chitinases and their participation in several diseases. The patents available also signify the extended role and effectiveness of chitinase inhibitors in the prevention and treatment of various diseases viz. asthma, acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer. In this regard, extensive pre-clinical and clinical investigations are required to develop some novel, potent and selective drug molecules for the treatment of various inflammatory diseases, allergies and cancers in the foreseeable future. Conclusion: In conclusion, chitinases can be used as potential biomarkers in prognosis and diagnosis of several inflammatory diseases and allergies and the design of novel chitinase inhibitors may act as key and rational scaffolds in designing some novel therapeutic agents in the treatment of variety of inflammatory diseases.