Abstract
Background: Diabetes mellitus, a chronic disease, has grown wide concern in today's world. Majority of the world’s population is affected by this disease. All the existing drugs have some side effects such as weight gain, risk of liver disease, skin problems etc. This situation demands the need of more and more potent drugs. Demand for new and faster acting drugs is great and as such it necessitated search for new drug targets. Keeping such a situation in view we wanted to screen out some non-toxic anti-diabetic molecules by applying computational tools. In the present work Protein Tyrosine Phosphate (PTP1B) was taken as the drug target and methoxime-3, 4-dephostatin (MXD) was chosen as the desired inhibitor.
Methods: 100 derivatives were generated as combinatorial library taking MXD as the parent molecule with the help of iLib diverse. Non-toxicity of the compounds was assured using online portal Mobyle@rpbs. Molecular docking was performed with the non-toxic derivatives using BiosolveIT LeadIT 2.1.3 and validated using Autodock 4.2. Activity profiling (IC50) was analysed with the help of QSAR study to find the potency of the best compound.
Results: ADMET screening confirmed that out of 100(hundred) derivatives generated, 95 (ninetyfive) were non-toxic and satisfy Lipinski rule. From molecular docking, the best pose was selected on the basis of their rank. Analysis of the result showed that Mol: 44 is the best option for PTP1B inhibition as it shows a good score of -30.5615. The other drug-likeness property for Mol: 44 have been screened with the help of Osiris Property Explorer. For QSAR model, activities were correlated with descriptors such as molar volume, parachor, molecular weight, logP and polarizability. The IC50 value of the compound Mol 44 which was found to have the highest score is 0.04µM which was moderate to that of controls.
Conclusion: Therefore the designed analogue of methoxime-3, 4-dephostatin, Mol: 44 (5-(4-{2,3- dihydroxy-5-[(E)-(methoxy-imino)methyl]phenyl}piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione) was found to have increased efficacy than the parent compound and also the known inhibitors reported. Thus, Mol: 44, a derivative of Methoxime-3, 4-dephostatin may be considered as an antidiabetic drug lead followed by in vitro and in vivo validation in future. If confirmed, the lead will be able to meet up some of the challenges of present diabetes treatment. Thus the study is of immense significance.
Keywords: Diabetes mellitus, PTP1B, Methoxime-3, 4-dephostatin, Docking, QSAR, Molecule 44.
Graphical Abstract
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