Abstract
Chemometrics study that relates biological activity to physicochemical descriptors of a molecule and the prediction of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties in advance are important steps in drugs discovery. In this study, a chemometrics approach was employed on some molecules (inhibitors) of norepinephrine transporter to assess their inhibitory potencies, interactions with the receptor and predict their ADMET/pharmacokinetic properties for identification of novel antipsychotic drugs. The molecules were optimized by using density functional theory at the basis set of B3LYP/6-31G*. The genetic function algorithm technique was used to generate a statistically significant model with a good correlation coefficient R2Train = 0.952 Cross-validated coefficient Q2cv = 0.870, and adjusted squared correlation coefficient R2adj = 0.898. The molecular docking simulation using a neurotransmitter transporter receptor (PDB Code 2A65) revealed that three inhibitors (molecule No 38, 44 and 12) exhibited the highest binding affinity of − 10.3, − 9.9 and − 9.3 kcal/mol, respectively, were observed to inhibit the target by forming strong hydrogen bonds with hydrophobic interactions. The physicochemical and ADMET/pharmacokinetic properties result showed that these three molecules are orally bioavailable, high gastrointestinal absorption, good permeability and non-inhibitors of CYP3A4 and CYP2D6 except for molecule No 38. Also, Molecules No 38 and 44 proved to be non-substrate of P-glycoprotein and nontoxicity to a human ether-a-go-go-related gene with predicted hERG toxicity endpoints (pIC50 < 6) and low ADMET_Risk (< 7.0). The results of this study would provide physicochemical and pharmacokinetics properties needed to identify potent antipsychotic drugs and other relevant information in drug discovery.
Highlights
Psychotic disorders are a group of serious illnesses that affect the mind, and a worldwide mental health challenge which occurred in a person whose mental functioning is impaired to interfere with their capacity to meet the basicElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.1 3 Vol.:(0123456789)Journal of the Iranian Chemical Society (2020) 17:1953–1966Norepinephrine (NE) is a neurotransmitter, a crucial neurochemical messenger employed in central noradrenergic and peripheral sympathetic synapses [6] responsible for the reuptake of released norepinephrine (NE) into nerve terminals in the brain
The aim of this study is to develop statistically acceptable quantitative structure activity relationship models, using molecular docking simulation to elucidate binding interactions between the molecules and norepinephrine transporter (NET), biological target and to predict their adsorption–distribution–metabolism–excretion–toxicity (ADMET)/pharmacokinetics properties and subsequently compare the results obtained with that of known antipsychotic drugs
The absorption, distribution, metabolism, excretion and toxicity properties predictions, as well as pharmacokinetic evaluation, are major steps for drugs targeting the central nervous system (CNS) because the ability of CNS drugs to penetrate the blood–brain barrier is very critical in metabolism the drug
Summary
Norepinephrine (NE) is a neurotransmitter, a crucial neurochemical messenger employed in central noradrenergic and peripheral sympathetic synapses [6] responsible for the reuptake of released norepinephrine (NE) into nerve terminals in the brain. Dysregulation of this neurotransmitter is associated with many debilitating psychotic disorders and mental illnesses [7]. Insilco methods including quantitative structure–activity relationship studies (QSARs), molecular docking and absorption–distribution–metabolism–excretion–toxicity (ADMET) properties/pharmacokinetics studies are key steps employing in drug development and discovery processes [9]. It is worthy to note that computerassisted drug design using Insilco methodology has been of great importance in the identification and development of novel medications for the treatment of antipsychotic diseases and other ailments [11]
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