Computational Approach for the Design of Novel Tankyrase Inhibitors: A Rational Study based on Pharmacophore and Atom based 3D QSAR

Aim/Background: The anomalous production of dihydrotestosterone (DHT) observed in benign prostatic hyperplasia and prostate cancer particularly in tissues of the prostate gland. The primary male sex hormone, testosterone (T) is improved to a metabolite in cells by 5a-reductase (5aR) type II enzyme through NADPH. A metabolite is DHT which is more potent than T. Drug therapy is the best alternative for the treatment of benign prostatic hyperplasia (BPH). Drug therapy act by dropping the DHT formation through inhibiting the 5aR enzyme. Thus, this research work was undertaken to design a novel 5aR enzyme inhibitor by pharmacophore and Atom-based 3D QSAR technique. Materials and Methods: A dataset of twenty-nine ligands available with IC 50 chosen from the literature. Schrodinger molecular modelling software is having, phase 3.0 module implicated for generation of pharmacophore models. Results: Pharmacophore hypothesis with five features having two H-bond acceptors and three hydrophobic group was developed, i.e., AAHHH.715. This Pharmacophore hypothesis regarded as the finest one. This hypothesis resulted into statistically significant three-dimensional QSAR model. The statistical parameters were found to be 0.9804 as r2 value and 0.8321as q2 value. Out of 29 ligands, 23 ligands assigned as training set and 6 ligands as a test set. The squared correlation coefficient between training and test sets based on actual and predicted values were observed to be 0.96 and 0.87 respectively. Conclusion: The 5aR enzyme inhibitors predicting requirements can be done by this built model.

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“…The ligands were separated on the basis of the activity threshold value into active and inactive sets. 21…”

Section: Pharmacophore Hypothesis Generationmentioning

confidence: 99%

“…The training set (23) was used to create atom-based QSAR models for the selected hypothesis using three PLS factors. The remaining molecules took under test set 21.…”

mentioning

confidence: 99%

Pharmacophore and Atom Based 3D QSAR Studies on the Novel 5-Alpha-Reductase Inhibitors

Shah¹,

Lobo

Nandakumar

et al. 2018

IJPER

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3D-QSAR and Pharmacophoric study on 2,6-Disubstituted Thiazolo [4,5-b] Pyridines as H3 Receptor Antagonists

Jain,

Bharti,

Jagan

et al. 2023

RJPT

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Histamine H3 receptor antagonist (H3RA) is a promising therapeutic for CNS disorders including attention deficit hyperactivity disorder [ADHD], sleep disorders, epilepsy, schizophrenia and obesity. 2,6-Disubstituted thiazolo[4,5-b]pyridines reported for their H3 receptor antagonistic activity were selected for three dimensional quantitative structure activity relationship (3D-QSAR) and pharmacophoric study in order to establish structure activity relationship quantitatively and essential structural features. In the current study, VLife Molecular Design Suite software (VlifeMDS) was used for QSAR and biophore studies. Pharmagist (web based server) was used for pharmacophoric study. Partial least square regression (PLSR) analysis showed r2= 0.7902, q2=0.6449 and pred_r2= 0.6650. In this model steric [S_138, S_826] and electrostatic descriptors [E_243, E_652] are involved to play an important role in eliciting biological activity. It showed good internal and external prediction. The contour plots provided further insight of the relationship between structural features of substituted thiazolo[4,5-b]pyridine derivatives and their activities which should be applicable to design newer potential H3R inhibitors. In addition with these studies, pharmacophoric models were also produced using Molsign (VLifeMDS) and Pharmagist (web based server). The identified pharmacophore features are two aromatic and two hydrogen bond acceptor with Molsign whereas common pharmacophoric features with Pharmagist are two aromatic, two hydrophobic and four hydrogen bond acceptors. The present work may be useful for further lead optimization and designing of potent H3 receptor antagonists.

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Computational Approach for the Design of Novel Tankyrase Inhibitors: A Rational Study based on Pharmacophore and Atom based 3D QSAR

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Pharmacophore and Atom Based 3D QSAR Studies on the Novel 5-Alpha-Reductase Inhibitors

Pharmacophore and Atom Based 3D QSAR Studies on the Novel 5-Alpha-Reductase Inhibitors

3D-QSAR and Pharmacophoric study on 2,6-Disubstituted Thiazolo [4,5-b] Pyridines as H3 Receptor Antagonists

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