Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Abstract

We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis ( Mycobacteria belonging to the Mycobacterium avium-M. intracellulare complex are responsible for opportunistic infections in immunocompromised patients, especially those with HIV infection (29), and there is a need for new drugs that can be used for treatment and prophylaxis. Quinolones are good candidates because of their broad antibacterial spectrum, which includes atypical mycobacteria (16,22,25,30), together with their good tissue distribution and intracellular concentration (2). Ciprofloxacin and sparfloxacin are the only quinolones currently used against M. avium-M. intracellulare complex infection, but the incidence of strains resistant to these compounds is increasing, and there is a need for new derivatives.In addition to in vitro and in vivo tests, which are timeconsuming for the M. avium-M. intracellulare complex, powerful methodologies for drug design and drug database screening and selection are now available (7,19). Equation systems linking structure and activity (QSAR studies) are particularly relevant, and application of the mathematical models thereby obtained to large libraries of computer-generated compounds is known as virtual computational screening (5, 24). An important feature in this method is the use of good structural descriptors that are representative of the molecular features responsible for the relevant biological activity; a very useful technique for describing molecular structure is molecular topology, a two-dimensional QSAR method which takes into account the internal atomic arrangement of compounds. The structure of each molecule is represented by specific subsets of topological indices (TIs). Klopman et al. first developed computer-based predictive models to characterize anti-M. avium-M. intracellulare complex activity (20,21,23). The aim of this study was to develop new QSAR models, based on TIs, statistical linear discriminant analysis (LDA), and multilinear regression (MLR) in order to predict the in vitro activity and MICs of quinolones against the M. avium-M. intracellulare complex. MATERIALS AND METHODSThe study involved a number of steps, which are described in the following paragraphs.Obtaining structural descriptors by molecular topology. A database of 158 quinolones with known anti-M. avium-M. intracellulare complex activities has been built up from several articles by Klopman et al. (20,21,23). Each quinolone was characterized by a set of 145 TIs specific to each molecule. We used the topological descriptors provided by MOLCONN-Z software, version 3.50 (L. H. Hall, Eastern Nazarene College, Quincy...

Usefulness of various antibiotics against Mycobacterium avium-intracellulare, measured by their mutant prevention concentration

“…These findings corroborate those obtained in animal models, where moxifloxacin exhibits good activity that increases in association with other drugs [27,28]. Studies using molecular topology suggest that gatifloxacin and moxifloxacin are the most active quinolones against this pathogen [29], although the structure of the antibiotic has also been associated with the capacity for generating resistant mutants as a function of the dose administered [30].…”

Diversity in Medicinal Chemistry Space

“…The molecule is represented by a vector whose components are continuous valued properties. The wide application of QSAR has led to a large number of molecular descriptors that have been successfully used to interpret biological activities [109][110][111][112][113][114][115][116][117][118][119].…”

Anti-leishmanial and anti-trypanosomal activities of 1,4-dihydropyridines: In vitro evaluation and structure–activity relationship study

“…11 Many works using graph-theoretical approaches have been reported for the design of new drugs, to control toxicity parameters and to find common structural patterns of known drugs. The successful design of drugs like analgesics, 12 anti-virals, 13 anti-bacterials, 14 and anti-mycobacterials 15 have been reported using this method.…”