Abstract
The enzyme β-1,3-glucan synthase, which catalyzes the synthesis of β-1,3-glucan, an essential and unique structural component of the fungal cell wall, has been considered as a promising target for the development of less toxic anti-fungal agents. In this study, a robust pharmacophore model was developed and structure activity relationship analysis of 42 pyridazinone derivatives as β-1,3-glucan synthase inhibitors were carried out. A five-point pharmacophore model, consisting of two aromatic rings (R) and three hydrogen bond acceptors (A) was generated. Pharmacophore based 3D-QSAR model was developed for the same reported data sets. The generated 3D-QSAR model yielded a significant correlation coefficient value (R2 = 0.954) along with good predictive power confirmed by the high value of cross-validated correlation coefficient (Q2 = 0.827). Further, the pharmacophore model was employed as a 3D search query to screen small molecules database retrieved from ZINC to select new scaffolds. Finally, ADME studies revealed the pharmacokinetic efficiency of these compounds.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2589-3) contains supplementary material, which is available to authorized users.
Highlights
Invasive fungal infections have emerged as the major causes of morbidity and mortality associated with cancer chemotherapy, organ transplant, HIV infection, hematopoietic stem cell transplant, and intensive care hospitalization (Walsh et al 1992; Groll et al 1996; Minamoto and Rosenberg 1997; Sahbudak et al 2015; Kanamori et al 2015; Cabezas-Quintario et al 2016; Kennedy et al 2016)
Pharmacophore modeling and 3D‐QSAR studies The pharmacophore models were constructed by selecting a minimum of four and a maximum of five pharmacophoric sites
From a list of 9 variant combinations a total of 5887 five-featured Common pharmacophore hypothesis (CPH) belonging to eight types, AAHRR, AHHRR, AAAAR, AAARR, AAAHH AAAAH, AAAHR, and AAHHR were subjected to rigorous scoring analysis with respect to actives using default parameters for site, vector, and volume
Summary
Invasive fungal infections have emerged as the major causes of morbidity and mortality associated with cancer chemotherapy, organ transplant, HIV infection, hematopoietic stem cell transplant, and intensive care hospitalization (Walsh et al 1992; Groll et al 1996; Minamoto and Rosenberg 1997; Sahbudak et al 2015; Kanamori et al 2015; Cabezas-Quintario et al 2016; Kennedy et al 2016). Only three structural classes of drugs: polyenes, azoles, and echinocandins are available as therapeutic options for such infections (Roemer and Krysan 2014). The polyenes like amphotericin B are the oldest class of antifungal drugs, which are preferred for treating systemic infections, whereas the most widely used class of antifungal drugs are Azoles (Maertens and Boogaerts 2000; Della Pepa et al 2016). The echinocandins are the most recent addition to the available range of antifungal agents (Kitamura 2010; Matejuk et al 2010; Moudgal and Sobel 2010). These compounds have emerged as an important therapeutic option against candidiasis as they exhibit broad fungicidal activity against Candida spp. These compounds have emerged as an important therapeutic option against candidiasis as they exhibit broad fungicidal activity against Candida spp. (Roemer and Krysan 2014).
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