The identification of c-Abl inhibitors as potential agents for Parkinson's disease: a preliminary in silico approach.

Parkinson's disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were - 11.8 kcal/mol, - 11.8 kcal/mol, and - 10.8 kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski's rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100 ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.

In-silico screening of Acacia pennata and Bridelia retusa reveals pinocembrin-7-O-ß-D-glucopyranoside as a promising ß-lactamase inhibitor to combat antibiotic resistance.

The ß-lactamase of Pseudomonas aeruginosa is known to degrade ß-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum ß-lactamase in a clinical isolate of P. aeruginosa, the bacterium has become multi-drug resistant. In this study, we aim to identify new ß-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7-O-ß-D-glucopyranoside (P7G) (-9.6 kcal/mol) from Acacia pennata and ellagic acid (EA) (-9.2 kcal/mol) from Bridelia retusa had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 (Ser62, Asn125, Asn163, Thr209, and Ser230) and 4 (Lys65, Ser123, Asn125, and Glu159) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with ß-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of ß-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of A. pennata as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the ß-lactamase of P. aeruginosa.Communicated by Ramaswamy H. Sarma.

Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the substantia nigra of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.