Virtual Screening Identification of Nonfolate Compounds, Including a CNS Drug, as Antiparasitic Agents Inhibiting Pteridine Reductase

Abstract

Folate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic drug candidates for combined therapy with dihydrofolate reductase (DHFR) inhibitors. To identify new molecules with specificity for PTR1, we carried out a virtual screening of the Available Chemicals Directory (ACD) database to select compounds that could interact with L. major PTR1 but not with human DHFR. Through two rounds of drug discovery, we successfully identified eighteen drug-like molecules with low micromolar affinities and high in vitro specificity profiles. Their efficacy against Leishmania species was studied in cultured cells of the promastigote stage, using the compounds both alone and in combination with 1 (pyrimethamine; 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine). Six compounds showed efficacy only in combination. In toxicity tests against human fibroblasts, several compounds showed low toxicity. One compound, 5c (riluzole; 6-(trifluoromethoxy)-1,3-benzothiazol-2-ylamine), a known drug approved for CNS pathologies, was active in combination and is suitable for early preclinical evaluation of its potential for label extension as a PTR1 inhibitor and antiparasitic drug candidate.

3D-QSAR based pharmacophore modeling and virtual screening for identification of novel pteridine reductase inhibitors

“…The diverse inhibitor molecules of PTR1 from L. major reported in literature with experimentally determined K i values were selected for 3D-QSAR studies [11][12][13][14][15][16]. The inhibitor molecules were divided into training and test set so as to cover varied range of the binding affinities and structural diversity.…”

“…R/R 1 and R 2 are the side chains of the scaffolds. The molecules selected as test set with their respective K i values are shown in bold [11][12][13][14][15][16] Recently, various rational structural techniques like structure-based drug design have been used to identify inhibitors against this enzyme [11][12][13][14][15][16][17][18]. This further necessitates exploration of the binding preferences of the known inhibitors in the context of structure activity relationship and the identification of potential novel lead molecules against PTR1.…”

Structure-based virtual screening and characterization of a novel IL-6 antagonistic compound from synthetic compound database

“…After evaluation of these fragments offered by Ludi, the mode of primitive molecule candidates was obtained by expanding these fragments. Finally, potential antagonistic compounds were screened out from 3D-Available Chemicals Directory (ACD) and MDL Drug Data Report (MDDR) libraries 29,30. All the molecules were visualized and analyzed using the InsightII (2000) software (Accelrys lnc., San Diego, CA, USA) running on an Octane2 R12000 Silicon Graphics workstation.…”

2-Amino-1,3,4-thiadiazoles as prospective agents in trypanosomiasis and other parasitoses

“…Thus, PTR1 is a promising drug target for the treatment of African trypanosomiasis (82,83). Some 2-amino-1,3,4-thiadiazole derivatives were identified as selective L. major PTR1 (LmPTR1) inhibitors and antileishmanial agents in the combination with DHFR inhibitors (84). T. brucei PTR1 (TbPTR1) shares 50 % amino acid sequence identity with LmPTR1, and (Table I) (58).…”