Molecular Dynamics Simulation and Pharmacoinformatic Integrated Analysis of Bioactive Phytochemicals from Azadirachta indica (Neem) to Treat Diabetes Mellitus

Abstract

Diabetes mellitus is a chronic hormonal and metabolic disorder in which our body cannot generate necessary insulin or does not act in response to it, accordingly, ensuing in discordantly high blood sugar (glucose) levels. Diabetes mellitus can lead to systemic dysfunction in the multiorgan system, including cardiac dysfunction, severe kidney disease, lowered quality of life, and increased mortality risk from diabetic complications. To uncover possible therapeutic targets to treat diabetes mellitus, the in silico drug design technique is widely used, which connects the ligand molecules with target proteins to construct a protein-ligand network. To identify new therapeutic targets for type 2 diabetes mellitus, Azadirachta indica is subjected to phytochemical screening using in silico molecular docking, pharmacokinetic behavior analysis, and simulation-based molecular dynamic analysis. This study has analyzed around 63 phytochemical compounds, and the initial selection of the compounds was made by analyzing their pharmacokinetic properties by comparing them with Lipinski’s rule of 5. The selected compounds were subjected to molecular docking. The top four ligand compounds were reported along with the control drug nateglinide based on their highest negative molecular binding affinity. The protein-ligand interaction of selected compounds has been analyzed to understand better how compounds interact with the targeted protein structure. The results of the in silico analysis revealed that 7-Deacetyl-7-oxogedunin had the highest negative docking score of −8.9 Kcal/mol and also demonstrated standard stability in a 100 ns molecular dynamic simulation performed with insulin receptor ectodomain. It has been found that these substances may rank among the essential supplementary antidiabetic drugs for treating type 2 diabetes mellitus. It is suggested that more in vivo and in vitro research studies be carried out to support the conclusions drawn from this in silico research strategy.

Identification of antidiabetic inhibitors from Allophylus villosus and Mycetia sinensis by targeting α-glucosidase and PPAR-γ: In-vitro, in-vivo, and computational evidence

“…The RSMF value is also used to figure out how much the protein–ligand complex changes over time. In this investigation, we used the Schrödinger package software (Desmond Application) to run a 100-ns Molecular Dynamic Simulation (MDS) with the physiological and physicochemical parameters of interest ( Abdullah et al, 2023 , Ahmed et al, 2023 , Andalib et al, 2023 , Sohel et al, 2022 ). There have been different ways to look at this simulation trajectory of the simulation tool.…”

Amazon Plant‐Derived Compounds Suppressing Dengue NS5 Protein: Insights from Computational Drug Development and Network Pharmacology Approach

“…Using such framework, the predefined TIP3P aqueous strategy to establish a predetermined volume having the orthorhombic periodic bounding box shape divided through a space of 10 Å. Recommended ions, such as 0+ and 0,15 M salt (Na+ and Cl−), have been chosen as well as dispersed at randomization across its chemical solvents environment to neutralize electric power in its structure [40,41] . After building its solvency proteins structures containing agonist combinations, the system's framework subsequently reduced as well as comfortable utilizing the protocol carried out applying force field constants OPLS3e included inside the Desmond package [42] .…”

“…Recommended ions, such as 0 + and 0,15 M salt (Na + and ClÀ ), have been chosen as well as dispersed at randomization across its chemical solvents environment to neutralize electric power in its structure. [40,41] After building its solvency proteins structures containing agonist combinations, the system's framework subsequently reduced as well as comfortable utilizing the protocol carried out applying force field constants OPLS3e included inside the Desmond package. [42] Every Isothermal-Isobaric ensemble (NPT) assembly which utilized overall Nose-Hoover temperatures combinations as well as its isotropic technique was kept around 300 K as well as one atmospheric pressure (1,01325 bar) as well as were followed by 50 PS grabbing pauses using an efficiency of 1.2 kcal/mol.…”

Waste to Medicine: Evidence from Computational Studies on the Modulatory Role of Corn Silk on the Therapeutic Targets Implicated in Type 2 Diabetes Mellitus

“…Natural products, plants, and plant fractions may be assessed against different targets implicated in disease emergence (and in this case, T2DM), such as key enzymes and genes, thus allowing for a comprehensive understanding of the antidiabetic potentials of CS typically against these targets through this approach [23,29]. Molecular dynamics (MD) simulation on the other hand, being a powerful computational technique, is used to the study the behaviour and interactions of atoms and molecules over time [32,33]. The approach similarly provides insight into protein-ligand interactions and the MoA of therapeutic agents, which can prove useful in the discovery and development of therapeutic agents, particularly T2DM [33][34][35][36].…”

“…Molecular dynamics (MD) simulation on the other hand, being a powerful computational technique, is used to the study the behaviour and interactions of atoms and molecules over time [32,33]. The approach similarly provides insight into protein-ligand interactions and the MoA of therapeutic agents, which can prove useful in the discovery and development of therapeutic agents, particularly T2DM [33][34][35][36]. The integration of various technologies, particularly NP, molecular docking, and MD simulation, as adopted in this study, should provide information towards identifying novel therapeutic agents from CS, which can be discovered and/or developed as alternative agents for the management of T2DM [37].…”