Cheminformatic designing of de novo inhibitors to 3-methyl adenine DNA glycosylase I (LiTagA) from Leptospira interrogans serovar lai strain 56601

Abstract

Leptospirosis is a worldwide waterborne zoonosis caused by Leptospira interrogans serovar lai strain 56601 and no specific antibiotics are available to effectively treat the disease to date. The enzyme 3-methyladenine-DNA glycosylase I (LiTagA), which excises 3-methyadenine and 3-methylguanine from alkylated DNA, is an indispensable component for the survival of the bacteria strain, and the absence of the enzyme in human makes it a promising chemotherapeutic target for antileptospiral treatments. In the present study, 578 non-redundant analogs of a few numbers of 3-alkyladenines, experimentally reported inhibitors to the enzyme, were retrieved from the NCI database and their binding affinities on the enzyme (modeled, solvated, and energy minimized at close quarters of physiologic conditions) were screened by means of PyRx—a high throughput virtual screening tool—and AutoDock. Using a lead identified from the studies as a seed, a small focussed combinatorial library containing 200 de novo inhibitors to the enzyme was generated and the compounds were subjected to affinity filter, bioavailability filter, and toxicity filter by means of an array of computational tools. Combined comprehensive analysis on the data obtained from the various filters brought out few numbers of efficient de novo inhibitors to the Leptospira interrogans LiTagA enzyme and also revealed that 5-H-indeno[1,2-b]pyridine system flanked by cationic and anionic chemical moieties at sites 9th and 12th positions, respectively, is an essential skeleton for the highly potent inhibitors to the enzyme. Moreover, implications of the studies on designing drug-likeness de novo inhibitors to protein targets have also been discussed in detail.