In silico screening of Annona Muricata L. Leaf constituents and derivatives towards selected targets of Type 2 Diabetes Mellitus

BACKGROUND@#Type 2 diabetes mellitus, or T2DM, is one of the world's most chronic health problems that is linked to numerous deaths and high health care expenses. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), protein-tyrosine phosphatase 1B (PTP1B) and mono-ADP-ribosyl transferase sirtuin-6 (SIRT6) were among the novel proteins and focus targets of diabetes research. Annona muricata is a commonly used natural remedy for several illnesses, including type 2 diabetes mellitus. However, most of these traditional claims have received few molecular evaluations.@*OBJECTIVES@#This investigated the phytoconstituents and derivatives of the leaves of A. muricata by evaluating their binding profiles towards selected novel T2DM-related protein targets through in silico methods.@*METHODOLOGY@#This study screened the potential lead compounds from the leaves of A. muricata by evaluating the binding energies of the parent compounds and derivatives with the targets compared to the native ligands and known substrates through molecular docking simulations. Additionally, pharmacokinetic, physicochemical properties, and binding interactions were also assessed using several software programs and online databases.@*RESULTS@#Out of the 8 selected parent compounds of Annona muricata, a total of 672 derivatives were designed, tested, and compared against the controls for at least one of the three protein targets. Among these, 280 derivatives exhibited more negative binding energies than controls in each protein target.@*CONCLUSION@#The designed derivatives can be synthesized and further investigated for potential biological effects towards 11β-HSD1, PTP1B, and SIRT6 through in vitro and in vivo experiments.

Computer-aided screening for potential inhibitory compounds against a Klebsiella pneumoniae local isolate containing SHV-1 and CTX-M antibiotic resistance genes

Background@#Extended-spectrum beta-lactamases (ESBLs), which allow bacteria to become resistant to commonly used antibiotics against common pathogens such as Klebsiella pneumoniae, are a significant public health concern as their presence severely limits treatment options. Discovery and development of new drug entities are critical to effectively combat infections with these increasingly common antibiotic-resistant variants. @*Objective@#Computational approaches can accelerate and reduce the cost of the discovery phase by screening for inhibitors of “druggable” pathogen enzyme targets in silico. In this study, protein structures of the ESBL enzymes SHV-1 and CTX-M-15 were used as targets in molecular docking experiments to identify potential inhibitors for K. pneumoniae. @*Methodology@#5000 compounds from the Enamine Real HTS compound database were screened in silico for binding to SHV-1 and CTX-M-15. Twenty-six (26) compounds that were identified to have more favorable interactions compared to Avibactam, a known inhibitor of the target proteins, were tested for cytotoxic activities in vivo using Resazurin Microtiter Assay (REMA) against a K. pneumoniae clinical isolate containing both SHV-1 and CTX-M-15 resistance genes. @*Results and Conclusion@#Despite favorable binding energies in in silico screening, most of the compounds exhibited negligible inhibition on the growth of the K. pneumoniae clinical isolate in in vitro assays. This may be attributed to the fact that a phenotypic whole-cell assay, instead of an enzyme-targeted assay, was used for validation. Cell permeability requires a different set of molecular parameters which were not part of the study. Doxorubicin exhibited the highest in vitro bactericidal activity against this strain, which agrees with its known activity against many other bacterial pathogens and may be a promising compound for further lead optimization.