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QSAR Evaluations to Unravel the Structural Features in Lysine-Specific Histone Demethylase 1A Inhibitors for Novel Anticancer Lead Development Supported by Molecular Docking, MD Simulation and MMGBSA

Authors :
Rahul D. Jawarkar
Ravindra L. Bakal
Nobendu Mukherjee
Arabinda Ghosh
Magdi E. A. Zaki
Sami A. AL-Hussain
Aamal A. Al-Mutairi
Abdul Samad
Ajaykumar Gandhi
Vijay H. Masand
Source :
Molecules, Vol 27, Iss 15, p 4758 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

Using 84 structurally diverse and experimentally validated LSD1/KDM1A inhibitors, quantitative structure–activity relationship (QSAR) models were built by OECD requirements. In the QSAR analysis, certainly significant and understated pharmacophoric features were identified as critical for LSD1 inhibition, such as a ring Carbon atom with exactly six bonds from a Nitrogen atom, partial charges of lipophilic atoms within eight bonds from a ring Sulphur atom, a non-ring Oxygen atom exactly nine bonds from the amide Nitrogen, etc. The genetic algorithm–multi-linear regression (GA-MLR) and double cross-validation criteria were used to create robust QSAR models with high predictability. In this study, two QSAR models were developed, with fitting parameters like R2 = 0.83–0.81, F = 61.22–67.96, internal validation parameters such as Q2LOO = 0.79–0.77, Q2LMO = 0.78–0.76, CCCcv = 0.89–0.88, and external validation parameters such as, R2ext = 0.82 and CCCex = 0.90. In terms of mechanistic interpretation and statistical analysis, both QSAR models are well-balanced. Furthermore, utilizing the pharmacophoric features revealed by QSAR modelling, molecular docking experiments corroborated with the most active compound’s binding to the LSD1 receptor. The docking results are then refined using Molecular dynamic simulation and MMGBSA analysis. As a consequence, the findings of the study can be used to produce LSD1/KDM1A inhibitors as anticancer leads.

Details

Language :
English
ISSN :
14203049
Volume :
27
Issue :
15
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.33c24f28429b457cb18ad11f3a4b7291
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules27154758