Design of novel compounds with the potential of dual PPARγ/α modulation for the management of metabolic syndrome

This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR) partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPAR fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPAR and/or _LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.peer-reviewe

The determination of the effect(s) of solute carrier family 22‑member 2 (SLC22A2) haplotype variants on drug binding via molecular dynamic simulation systems

Single nucleotide polymorphisms detected in the solute carrier member family-22 has been shown to result in a variable response in the treatment of type 2 diabetes mellitus with Metformin. This study predicted a three-dimensional protein structure for the SLC22A2 protein sequence using AlphaFold 2 and modelled five haplotypes within SLC22A2 protein structure observed in the Xhosa population of South Africa. The protein models were used to determine the effect(s) of haplotype variations on the transport function of Metformin and 10 other drugs by the SLC22A2 protein. Molecular dynamic simulation studies, molecular docking and interaction analysis of the five SLC22A2 haplotypes were performed in complex with the ligand 5RE in a POPC lipid bilayer to understand the mechanism of drug binding

Angiotensin-converting enzyme inhibitory activity of polyphenolic compounds from Peperomia pellucida (L) Kunth: An in silico molecular docking study

This study aimed to predict the potential activity and interaction conformation of polyphenolic compounds from Peperomia pellucida (L) Kunth (nine compounds) with angiotensin-converting enzyme (ACE) macromolecule by in silico molecular docking study. The crystal structure of ACE as a molecular target was obtained from the PDB database (PDB ID: 1UZF) with captopril as a native ligand. Molecular docking analysis was performed using AutoDockZn (100 docking runs) based on the active site of Zn2+, the central grid was placed on Zn2+ with a box size of 40Á × 40Á × 40Á and a center of 40.835Á × 34.382Á × 44.607Á for selective inhibitors (MCO702) with a spacing of 0.375Á. Based on the docking results demonstrated that the prediction of each polyphenol compounds from P. pellucida has the potential of active as ACE inhibitors, it was indicated that docking results of each compound has lower affinity compared to captopril (with binding affinity of −6.36 kcal/mol and the inhibition constant 21.81 μM), where the most moderate binding affinity (the most potential) was tetrahydrofuran lignin ((1R,2S,3S,5R)-3,5-bis(4-hydroxy- 3,5-dimethoxyphenyl)cyclopentane-1,2-diyl)bis-(methylene) diacetate) of −8.66 kcal/mol and the highest binding affinity (the less potential) was dillapiole (6-allyl-4,5-dimethoxybenzo[d][1,3]dioxole) of −4.99 kcal/mol, although with different forms of interaction, bond, and constant inhibition. Based on the interaction of ACE binding site, 5,6,7-trimethoxy-4-(2,4,5-trimethoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one showed the most similar interaction with the captopril ligand. These results are preliminary data for further research with predictions of target compound biological activity and interaction quickly, accurately, and inexpensively. Keywords: Angiotensin-converting enzyme, binding affinity, molecular docking, Peperomia pellucida (L) Kunth, polyphenolics

MOLECULAR DOCKING STUDIES OF RICINUS COMMUNIS PHYTOCHEMICALS AGAINST BETA-LACTAMASE FROM ENTEROCOCCUS FAECALIS AND STAPHYLOCOCCUS AUREUS

Objective: The objective of this study is to investigate the antibacterial activity of Ricinus communis phytochemicals against beta-lactamase from Enterococcus faecalis and Staphylococcus aureus through molecular docking studies. Methods: The three-dimensional (3D) structure of beta-lactamase from E. faecalis was modeled using modeler 9v9 and validated. The 3D structure of beta-lactamase from S. aureus (PDB ID: 1 GHP) was retrieved from PDB database. The 2D structures of 29 phytochemical compounds from the methanol leaf extracts of R. communis were drawn in ACD-Chemsketch and converted into 3D structures. The 3D structure of R. communis leaf compounds and cefotaxime (control) was virtually screened in the binding pockets of β-lactamase proteins from E. faecalis and S. aureus using FlexX docking program. Results: The docking studies revealed that ferulic acid and hyperoside exhibited promising minimum binding and docking energy that is closely related to the docking score of standard antibiotic cefotaxime. Conclusion: The result of the present study indicates that ferulic acid and hyperoside are potential compounds that could be effectively used in the treatment of infections caused by E. faecalis and S. aureus. However, further clinical studies are required to ascertain the antibacterial activity and potential toxic effects of ferulic acid and hyperoside in vivo.Â

Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters

Abstract: Persisters are a sub-population of genetically sensitive bacteria that survive antibiotic treatment by entering a dormant state. The emergence of persisters from dormancy after antibiotic withdrawal leads to recurrent infection. Indole is an aromatic molecule with diverse signalling roles, including a role in persister formation. Here we demonstrate that indole stimulates the formation of Escherichia coli persisters against quinolone antibiotics which target the GyrA subunit of DNA gyrase. However, indole has no effect on the formation of E. coli persisters against an aminocoumarin, novobiocin, which targets the GyrB subunit of DNA gyrase. Two modes of indole signalling have been described: persistent and pulse. The latter refers to the brief but intense elevation of intracellular indole during stationary phase entry. We show that the stimulation of quinolone persisters is due to indole pulse, rather than persistent, signalling. In silico docking of indole on DNA gyrase predicts that indole docks perfectly to the ATP binding site of the GyrB subunit. We propose that the inhibition of indole production offers a potential route to enhance the activity of quinolones against E. coli persisters

The calcium goes meow : effects of ions and glycosylation on Fel d 1, the major cat allergen

The major cat allergen, Fel d 1, is a structurally complex protein with two N-glycosylation sites that may be filled by different glycoforms. In addition, the protein contains three putative Ca2+ binding sites. Since the impact of these Fel d 1 structure modifications on the protein dynamics, physiology and pathology are not well established, the present work employed computational biology techniques to tackle these issues. While conformational effects brought upon by glycosylation were identified, potentially involved in cavity volume regulation, our results indicate that only the central Ca2+ion remains coordinated to Fel d 1 in biological solutions, impairing its proposed role in modulating phospholipase A2 activity. As these results increase our understanding of Fel d 1 structural biology, they may offer new support for understanding its physiological role and impact into cat-promoted allergy