Identification of lead compounds from large natural product library targeting 3C-like protease of SARS-CoV-2 using E-pharmacophore modelling, QSAR and molecular dynamics simulation

Background: HIV-1 integrase (IN) has been considered as an important target for the development of novel antiHIV-1 drugs. Objective: The aim of study is to design a novel groups of HIV IN inhibitors Method: In this study, we presented a novel series of 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives by structural modification of N-arylindole -diketoacids as a well-known group of IN inhibitors. Results: Based on in-vitro anti-HIV-1 activity in cell-based assay, compounds 5, 6a and 6k displayed moderate to good inhibitory activity with EC50 values of 4.14, 1.68 and 0.8 M, respectively. However, integrase inhibition assay showed that most of analogues did not have significant effects against integrase enzyme except compound 5 with IC50 value of 45 M. Our results indicated that compound 6k was the best one among synthesized compounds with an EC50 of 0.8 M and SI of 175. Docking and molecular dynamics simulation studies were also performed to provide some insights into probable mechanism of tested compounds. Conclusion: These findings suggest that 4-oxo-4,10-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylic acid derivatives may consider as promising lead compounds for development of new anti-HIV-1 drugs.

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High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach

Pharmaceuticals ◽

10.3390/ph14090937 ◽

2021 ◽

Vol 14 (9) ◽

pp. 937

Author(s):

Danish Iqbal ◽

Md Tabish Rehman ◽

Abdulaziz Bin Dukhyil ◽

Syed Mohd Danish Rizvi ◽

Mohamed F. Al Ajmi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Natural Product ◽

High Throughput ◽

High Throughput Screening ◽

Dynamics Simulation ◽

Potential Candidate ◽

Stable Conformation

Alzheimer’s disease (AD) is a progressive neurological disorder that affects 50 million people. Despite this, only two classes of medication have been approved by the FDA. Therefore, we have planned to develop therapeutics by multitarget approach. We have explored the library of 2029 natural product-like compounds for their multi-targeting potential against AD by inhibiting AChE, BChE (cholinergic pathway) MAO-A, and MOA-B (oxidative stress pathway) through in silico high-throughput screening and molecular dynamics simulation. Based on the binding energy of these target enzymes, approximately 189 compounds exhibited a score of less than −10 kcal/mol against all targets. However, none of the control inhibitors exhibited a binding affinity of less than −10 kcal/mol. Among these, the top 10 hits of compounds against all four targets were selected for ADME-T analysis. As a result, only F0850-4777 exhibited an acceptable range of physicochemical properties, drug-likeness, pharmacokinetics, and suitability for BBB permeation with high GI-A and non-toxic effects. The molecular dynamics study confirmed that F0850-4777 remained inside the binding cavity of targets in a stable conformation throughout the simulation and Prime-MM/GBSA study revealed that van der Waals’ energy (ΔGvdW) and non-polar solvation or lipophilic energy (ΔGSol_Lipo) contribute favorably towards the formation of a stable protein–ligand complex. Thus, F0850-4777 could be a potential candidate against multiple targets of two pathophysiological pathways of AD and opens the doors for further confirmation through in vitro and in vivo systems.

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