In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

Singh, Aarti; Paliwal, Sarvesh; Sharma, Manu; Mittal, Anupama; Sharma, Swapnil; Sharma, Jai Prakash

doi:10.1016/j.jmgm.2015.10.014

Cited by 14 publications

(10 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both compounds displayed moderate activity against C. tropicalis (MIC 90 = 7.17 and 4.61 μg/mL, respectively) and A. niger (MIC 90 = 4.44 and 4.31 μg/mL, respectively) in comparison with fluconazole with MIC 90 = 4.97 against C. tropicalis and 2.77 μg/mL against A. niger . On the other hand, 13 was shown to be more potent against C. albicans (MIC 90 = 5.15 μg/mL) than fluconazole (MIC 90 = 5.15 μg/mL), and both 13 and 14 exhibited better activity against C. parapsilosis (MIC 90 = 2.99 and 2.57 μg/mL, respectively) than the standard inhibitor (MIC 90 = 4.28 μg/mL) .…”

Section: Molecular Modeling Tools For the Discovery Of New Cyp51 Inhimentioning

confidence: 99%

Targeting CYP51 for drug design by the contributions of molecular modeling

Rabelo

Santos

Terra

et al. 2016

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles.

show abstract

Section: Molecular Modeling Tools For the Discovery Of New Cyp51 Inhimentioning

confidence: 99%

Targeting CYP51 for drug design by the contributions of molecular modeling

Rabelo

Santos

Terra

et al. 2016

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…In the current study, we have constructed a PiCYP51A model for the first time with the core region of PiCYP51 proteins (Figure 2), containing the most conserved fold structure reported in the other P450 proteins [16,17,18,21,22,23], including helices E, I, J and L. Each of these helices has at least two aromatic-ring-containing residues (Phe and/or Tyr) involved in the hydrophobic interacting with some specific receptor(s). On the other hand, the present PiCYP51A model also suggested the critical role of nitrogen (N) atoms in the azole and aromatic rings in the coordination bond formation, as experimentally reported for the ligand-heme Fe(II) interaction in PiCYP51A active site [4].…”

Section: Discussionmentioning

confidence: 99%

“…Virtual screening supported by large-scale chemical libraries has been developed to be an important tool in novel lead molecules discovery [16,17]. Ligand-based screening techniques have the advantage of finding lead molecules based on a set of pharmacophore elements derived from a specific functional ligand family [15,18,19,20].…”

Section: Introductionmentioning

confidence: 99%

“…Owing to the membrane-associated characteristics for all the eukaryotic CYP51s, it remains a challenge to solve their crystal structures. Homology modeling has been widely applied in three-dimensional model building of CYP51s to understand molecular interactions between inhibitors and target enzymes [17,21]. The crystal structure of M. tuberculosis CYP51 (MtCYP51) has been used in many CYP51 modeling studies [4,22,23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacophore-Based Virtual Screening of Novel Inhibitors and Docking Analysis for CYP51A from Penicillium italicum

et al. 2017

View full text Add to dashboard Cite

Sterol 14α-demethylases from Cytochrome P450 family (CYP51s) are essential enzymes in sterol biosynthesis and well-known as the target of antifungal drugs. The 3D structure of CYP51A from Penicillium italicum (PiCYP51A) was constructed through homology modeling based on the crystal structure of human CYP51A (PDB: 3LD6). Molecular dynamics (MD) simulation was operated to relax the initial model and followed by quality assessment using PROCHECK program. On the basis of the docking information on the currently available CYP51s with the patent demethylase inhibitors (DMIs), pharmacophore-based virtual screening combined with docking analysis was performed to pick out twelve new compounds from ZINC database. Six hits revealed in the ligand database suggested potential ability to inhibit PiCYP51A. Compared to patent fungicide triazolone, the top three lead compounds had similar or higher affinity with the target enzyme, and accordingly, exhibited comparable or lower EC50 values to P. italicum isolates. The results could provide references for de novo antifungal drug design.

show abstract

“…These three-dimensional modeled structures of protein imitate the interaction of enzyme substrate to provide the catalytic efficiency of enzymes [40, 41]. This progress has occurred due to new methodology to gather large amount of information in sequence and structure database and improved computational descriptions of protein energetics [42].…”

Section: Fatty Acid Biosynthesis and Acetyl-coamentioning

confidence: 99%

Lipid production and molecular dynamics simulation for regulation of accD gene in cyanobacteria under different N and P regimes

Kumar

Biswas

Singh

et al. 2017

Biotechnol Biofuels

View full text Add to dashboard Cite

BackgroundMicroalgae grown under different nutrient deficient conditions present a good source of natural lipids with applications for several types of biofuels. The expression of acetyl-CoA carboxylase gene can further provide an insight to the mechanisms leading to enhanced lipid production under such stresses. In this study, two nutrients viz. nitrogen and phosphorus were modulated to see its effect on lipid productivity in selected cyanobacteria and its correlation with Accase followed by molecular dynamics simulation.ResultsSelected cyanobacteria viz. Oscillatoria sp. (SP8), Anabaena sp. (SP12), Anabaena sp. (SP13), Microcoleus sp. (SP18), and Nostoc sp. (SP20) varied in their ability to accumulate lipids which ranged from a lowest of 0.13% in Anabaena sp. (SP13) to the maximum of 7.24% in Microcoleus sp. (SP18). Microcoleus sp. (SP18) also recorded highest lipid accumulation at both N (6 mM NaNO3) and P (0.20 mM K2HPO4) limiting conditions. The overall expression of accD was found to be upregulated in both Oscillatoria sp. (SP8) and Microcoleus sp. (SP18) for all nitrogen concentrations but was differentially regulated with both positive and negative induction under phosphorus stress conditions. Maximum induction was observed in Microcoleus sp. (SP18) at 0.20 mM K2HPO4. The obtained 3D structure of SP8 protein (21.8 kDa) showed six alpha helices, while SP18 protein (16.7 kDa) exhibited four alpha helices and four beta sheets. The phi (ϕ)/psi(ψ) angles of the amino acid residues observed in Ramachandran plot analysis showed that both SP8 and SP18 proteins were highly stable with more than 90% amino acids in allowed regions. The molecular dynamics simulation results also indicated the stability of ligand-bound protein complexes.ConclusionIt has been demonstrated that cyanobacterial isolates are affected differently by nutrient limitation leading to variation in their lipid productivity. The same has been revealed by the behavior of accD gene expression which was regulated more by nutrients concentrations rather than the organism. However, the ligand-bound protein complexes were stable throughout MD simulations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-017-0776-2) contains supplementary material, which is available to authorized users.

show abstract

In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent

Cited by 14 publications

References 41 publications

Targeting CYP51 for drug design by the contributions of molecular modeling

Targeting CYP51 for drug design by the contributions of molecular modeling

Pharmacophore-Based Virtual Screening of Novel Inhibitors and Docking Analysis for CYP51A from Penicillium italicum

Lipid production and molecular dynamics simulation for regulation of accD gene in cyanobacteria under different N and P regimes

Contact Info

Product

Resources

About