Identification of steroid-like natural products as antiplasmodial agents by 2D and 3D similarity-based virtual screening

Abstract

The emergence of drug resistance in to available antimalarial drugs has challenged current antimalarial treatments. New antimalarials, particularly those with novel mechanisms of action and no cross resistance to current drugs, are therefore urgently needed. To identify new growth inhibitors of, 2D and 3D similarity-based virtual screening methods were employed in parallel with an in-house database of steroid-type natural products using fusidic acid as a search query. The resulting hit compounds were further filtered based on the predicted partition coefficient, log . The virtual screening strategy resulted in the identification of nine new compounds that inhibited parasite growth with IC values of <20 μM. Four compounds exhibited IC values in the range of 1.39-3.45 μM and three of which showed a promising selectivity index. Further, the predicted ADME properties of the four most active compounds were found to be comparable to fusidic acid. These compounds can be further explored using structural modifications in the identification and development of more potent parasite growth inhibitors with improved selectivity.

Bioactivities and Structure–Activity Relationships of Fusidic Acid Derivatives: A Review

“…The IC 50 values of the four most active compounds 22-25 were 1.39, 1.76, 2.92, and 3.45 μM, respectively. Moreover, the predicted absorption, distribution, metabolism, and excretion (ADME) properties of these four compounds were comparable to FA (Pavadai et al, 2017).…”

Applications of Virtual Screening in Bioprospecting: Facts, Shifts, and Perspectives to Explore the Chemo-Structural Diversity of Natural Products

“…The investigation of the chemical space of natural products is an intelligent way to identify some classes of compounds, their bioactivity, and the structural scaffolds present in known active compounds (Opassi et al, 2018 ). Due to the high diversity of the derived structures of natural products containing modified functional groups; different strategies have been applied to investigate their chemical space, which include the modeling of hypothetical structural modification (Skinnider et al, 2017 ) and the application of less restrictive similarity-based cutoffs (Pavadai et al, 2017 ).…”

“…Shape-based similarity methods have been used in virtual screening workflows alone or combined with different computational techniques (Pavadai et al, 2017 ; Thireou et al, 2018 ). Pavadai et al applied shape-based and fingerprint-based similarity search against natural product libraries to find new steroid-like natural products as antiplasmodial agents using, as a search key, fusidic acid.…”

“…Pavadai et al applied shape-based and fingerprint-based similarity search against natural product libraries to find new steroid-like natural products as antiplasmodial agents using, as a search key, fusidic acid. The hit compounds were filtered based on the predicted partition coefficient, log P , and the authors identified nine new compounds that inhibited parasite growth with IC 50 values of <20 μM (Pavadai et al, 2017 ). Figure 4 exhibits an overview of the 3D shape-similarity search methods applied to identify compounds in chemical libraries with similar molecular shapes despite their different structures.…”

“…Based on these, the virtual screening strategies must investigate the chemical space of natural products, seeking to identify some classes of compounds with bioactivity or structural scaffolds present in known active molecules. Some of these screening strategies include applying less restrictive structural-based similarity cutoffs (Pavadai et al, 2017 ) and the modeling of hypothetically derived natural product structures (Skinnider et al, 2017 ). Regarding the application of molecular filters, some “bioactivity-likeness” criteria must be used with caution to avoid misleading screening or remotion of the important structural diversity of the compound libraries since the structural complexity of natural products situates them beyond the acceptable limits of some empirical rules determined by these filters.…”