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In-silico study of seaweed secondary metabolites as AXL kinase inhibitors.

ABSTRACT: AXL kinase is an attractive cancer target for drug design and it is involved in different cancers. A set of molecule databases with 1072 secondary metabolites from seaweeds were screened against the AXL kinase active site and eight molecules were shortlisted for further studies. From the docking analysis of the complexes, four molecules GA011, BE005, BC010, and BC005 are showing prominent binging. From the 100 ns of molecular dynamics simulations and ligand-bound complex MM-PBSA free energy analysis, two molecules BC010 (ΔG = -135.38 kJ/mol) and BE005 (ΔG = -141.72 kJ/mol) are showing molecule stability in the active site also showing very strong binding free energies. It suggests these molecules could be the potent molecules for AXL kinase.

SUBMITTER: Nagamalla L

PROVIDER: S-EPMC8848138 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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<i>In-silico study</i> of seaweed secondary metabolites as AXL kinase inhibitors.

Nagamalla Lavanya L Shanmukha Kumar J V JV Sanjay Chintakindi C Alsamhan Ali M AM Shaik Mohammed Rafi MR

Saudi journal of biological sciences 20211130 2

AXL kinase is an attractive cancer target for drug design and it is involved in different cancers. A set of molecule databases with 1072 secondary metabolites from seaweeds were screened against the AXL kinase active site and eight molecules were shortlisted for further studies. From the docking analysis of the complexes, four molecules GA011, BE005, BC010, and BC005 are showing prominent binging. From the 100 ns of molecular dynamics simulations and ligand-bound complex MM-PBSA free energy anal ...[more]

PMID: 35197734

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Project description:The species complex around the medicinal fungus Ganoderma lucidum Karst. (Ganodermataceae) is widely known in traditional medicines, as well as in modern applications such as functional food or nutraceuticals. A considerable number of publications reflects its abundance and variety in biological actions either provoked by primary metabolites, such as polysaccharides, or secondary metabolites, such as lanostane-type triterpenes. However, due to this remarkable amount of information, a rationalization of the individual Ganoderma constituents to biological actions on a molecular level is quite challenging. To overcome this issue, a database was generated containing meta-information, i.e., chemical structures and biological actions of hitherto identified Ganoderma constituents (279). This was followed by a computational approach subjecting this 3D multi-conformational molecular dataset to in silico parallel screening against an in-house collection of validated structure- and ligand-based 3D pharmacophore models. The predictive power of the evaluated in silico tools and hints from traditional application fields served as criteria for the model selection. Thus, the focus was laid on representative druggable targets in the field of viral infections (5) and diseases related to the metabolic syndrome (22). The results obtained from this in silico approach were compared to bioactivity data available from the literature. 89 and 197 Ganoderma compounds were predicted as ligands of at least one of the selected pharmacological targets in the antiviral and the metabolic syndrome screening, respectively. Among them only a minority of individual compounds (around 10%) has ever been investigated on these targets or for the associated biological activity. Accordingly, this study discloses putative ligand target interactions for a plethora of Ganoderma constituents in the empirically manifested field of viral diseases and metabolic syndrome which serve as a basis for future applications to access yet undiscovered biological actions of Ganoderma secondary metabolites on a molecular level.

Project description:BackgroundSecondary metabolites biosynthesized by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. In view of their relevance for natural product based drug discovery, identification of novel secondary metabolite natural products by genome mining has been an area of active research. A number of different tailoring enzymes catalyze a variety of chemical modifications to the polyketide or nonribosomal peptide backbone of these secondary metabolites to enhance their structural diversity. Therefore, development of powerful bioinformatics methods for identification of these tailoring enzymes and assignment of their substrate specificity is crucial for deciphering novel secondary metabolites by genome mining.ResultsIn this work, we have carried out a comprehensive bioinformatics analysis of methyltransferase (MT) domains present in multi functional type I PKS and NRPS proteins encoded by PKS/NRPS gene clusters having known secondary metabolite products. Based on the results of this analysis, we have developed a novel knowledge based computational approach for detecting MT domains present in PKS and NRPS megasynthases, delineating their correct boundaries and classifying them as N-MT, C-MT and O-MT using profile HMMs. Analysis of proteins in nr database of NCBI using these class specific profiles has revealed several interesting examples, namely, C-MT domains in NRPS modules, N-MT domains with significant homology to C-MT proteins, and presence of NRPS/PKS MTs in association with other catalytic domains. Our analysis of the chemical structures of the secondary metabolites and their site of methylation suggested that a possible evolutionary basis for the presence of a novel class of N-MT domains with significant homology to C-MT proteins could be the close resemblance of the chemical structures of the acceptor substrates, as in the case of pyochelin and yersiniabactin. These two classes of MTs recognize similar acceptor substrates, but transfer methyl groups to N and C positions on these substrates.ConclusionWe have developed a novel knowledge based computational approach for identifying MT domains present in type I PKS and NRPS multifunctional enzymes and predicting their site of methylation. Analysis of nr database using this approach has revealed presence of several novel MT domains. Our analysis has also given interesting insight into the evolutionary basis of the novel substrate specificities of these MT proteins.

Dataset Information

In-silico study of seaweed secondary metabolites as AXL kinase inhibitors.

Publications

<i>In-silico study</i> of seaweed secondary metabolites as AXL kinase inhibitors.

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