Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Purpose: To design dual inhibitors against Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) via pharmacoinformatics approach.Methods: Dual Drug Candidates (DDC) were designed and explored for their molecular interaction with several AD and T2DM targets. Pterostilbene, a natural anti-T2DM compound was coupled with different cholinesterase inhibitors to design DDC. Orisis Datawarrior online property calculator  tools, Autock 4.2 and Hex 5.1 were used to investigate the potency of all DDC relative to positive controls.Results: The study found that DDC2 (pterostilbene - methylene linker -octa hydro amino phenothiazine), DDC3 (pterostilbene - ethylene linker - N-phthalimide) and DDC5 (pterostilbene - carbonyl linker - 2-methyl-4-aminoquinoline) were the most promising out of all the DDCs. DDC2 showed strong molecular interaction with most of the AD and T2DM targets, including acetylcholinesterase, butrylcholinesterase, β-secretase, receptor for advanced glycation end products and ATP sensitive potassium channel, dipeptidyl peptidase IV and sodium glucose transport protien 2. The findings also revealed the amyloid anti-aggregation potential of DDC.Conclusion: The results show that DDC3 and DDC5 significantly interfer with the primary nucleation process of β amyloid. Thus, DDC2, DDC3 and DDC5 have strong anti-T2DM and anti-AD potential. Keywords: Type 2 Diabetes Mellitus, Alzheimer’s disease, Dual drug candidate, Amyloid-beta, Pterostilben

RHAMNETIN IS A BETTER INHIBITOR OF SARS-COV-2 2’-O-METHYLTRANSFERASE THAN DOLUTEGRAVIR: A COMPUTATIONAL PREDICTION

Background: The 2’-O-methyltransferase is responsible for the capping of SARS-CoV-2 mRNA and consequently the evasion of the host’s immune system. This study aims at identifying prospective natural inhibitors of the active site of SARS-CoV-2 2’O-methyltransferase (2’-OMT) through an in silico approach. Materials and Method: The target was docked against a library of natural compounds obtained from edible African plants using PyRx - virtual screening software. The antiviral agent, Dolutegravir which has a binding affinity score of -8.5 kcal mol−1 with the SARS-CoV-2 2’-OMT was used as a standard. Compounds were screened for bioavailability through the SWISSADME web server using their molecular descriptors. Screenings for pharmacokinetic properties and bioactivity were performed with PKCSM and Molinspiration web servers respectively. The PLIP and Fpocket webservers were used for the binding site analyses. The Galaxy webserver was used for simulating the time-resolved motions of the apo and holo forms of the target while the MDWeb web server was used for the analyses of the trajectory data. Results: The Root-Mean-Square-Deviation (RMSD) induced by Rhamnetin is 1.656A0 as compared to Dolutegravir (1.579A0). The average B-factor induced by Rhamnetin is 113.75 while for Dolutegravir is 78.87; the Root-Mean-Square-Fluctuation (RMSF) for Rhamnetin is 0.75 and for Dolutegravir is 0.67. Also at the active site, Rhamnetin also has a binding affinity score of -9.5 kcal mol−1 and forms 7 hydrogen bonds as compared to Dolutegravir which has -8.5 kcal mol−1 and forms 4 hydrogen bonds respectively. Conclusion: Rhamnetin showed better inhibitory activity at the target’s active site than Dolutegravir

In silico identification of the potential natural inhibitors of SARS-CoV-2 Guanine-N7 methyltransferase

This study aims at computationally identifying the potential natural inhibitors of the SARS-CoV-2 Guanine-N7 methyltransferase binding at the active sit

Data_Sheet_1_Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease.DOCX

<p>The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD). Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as β-secretase (BACE1) and mid-region amyloid-beta (Aβ) (PDBIDs: 2ZHV & 4XXD), respectively using molecular docking and dynamic simulation (MD) approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F) graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm) was much better compared to Solanezumab (0.7 nm). Moreover, the radius of gyration (Rg) results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab.</p

Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD). Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as β-secretase (BACE1) and mid-region amyloid-beta (Aβ) (PDBIDs: 2ZHV &amp; 4XXD), respectively using molecular docking and dynamic simulation (MD) approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F) graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm) was much better compared to Solanezumab (0.7 nm). Moreover, the radius of gyration (Rg) results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab

The development of peptide-based inhibitors for Tau aggregation as a potential therapeutic for Alzheimer’s disease

There are currently approximately 50 million individuals worldwide with dementia resulting in predicted global societal costs of up to US $1 trillion. Approximately 60-70% of these individuals have Alzheimer’s disease, which results in a chronic and insidious decline in memory. One of the main proteins that misfolds in this disease is Tau protein, which aggregates into toxic oligomers and neurofibrillary tangles. It is these aggregates, which cause damage to the brain resulting in dementia. As a result, it is imperative to be able to prevent or suppress the pathogenic aggregation of this protein, so the onset of dementia is halted or delayed, improving quality of life. Certain amino acid sequences in Tau such as VQIINK and VQIVYK play important roles in aggregation. Targeting these sequences can potentially prevent aggregation. This project aims to produce effective peptide inhibitors based on the human Tau peptide sequences VQIINK and VQIVYK, to specifically target pathogenic Tau aggregation. Using molecular docking softrware ‘ICM-Pro’ the potential binding locations of a variety of peptide candidates were computationally investigated to determine which will be most successful in a laboratory setting. Recombinant TauΔ1-250 was incubated in the prescense of heparin and subsequently aggregated to display highly ordered parallel, in-register β-strand structures; including fibrils and paired helical filaments presenting the characteristic twist under transmission electron microscope. This aggregation was achieved using of 20μM Tau at pH 7.4 in the presence of 20mM Tris buffer, 1mM DTT, 5μM Heparin, and 15uM ThT and incubated at 37 °C for 48 hours. The first generation of peptides AG01, AG02, AG02, AG02R4, AG02R5, AGR502, AG02PR5, AG02R6, AG02R9, AG02TAT, AG02ΔI, AG02ΔV inhibited approximately 50% of Tau aggregation determined by Thioflavin-T (ThT) fluorescence assay. The next generation, AG03 was slightly more effective, however when retroinverted (RI-AG03) inhibited over 90% of Tau aggregation, confirmed by Thioflavin-T fluorescence assay, transmission electron microscopy, circular dichroism and Congo red birefringence. RI-AG03 was determined to be stable in cells at therapeutic concentrations. After determining stability of RI-AG03 using SDS-PAGE, thermal circular dichroism and mass spectrometry, it was tested in vivo in rough eye Drosophila model. Results suggested that RI-AG03 partially rescued the rough eye phenotype in this model. This research demonstrates that retro-inverted peptide RI-AG03 is a potent inhibitor of Tau aggregation and can be further developed as a novel therapeutic for Tauopathies like Alzhimer’s Disease