Mechanistic Analysis of Chemically Diverse Bromodomain-4 Inhibitors Using Balanced QSAR Analysis and Supported by X-ray Resolved Crystal Structures

Abstract

Bromodomain-4 (BRD-4) is a key enzyme in post-translational modifications, transcriptional activation, and many other cellular processes. Its inhibitors find their therapeutic usage in cancer, acute heart failure, and inflammation to name a few. In the present study, a dataset of 980 molecules with a significant diversity of structural scaffolds and composition was selected to develop a balanced QSAR model possessing high predictive capability and mechanistic interpretation. The model was built as per the OECD (Organisation for Economic Co-operation and Development) guidelines and fulfills the endorsed threshold values for different validation parameters (R2tr = 0.76, Q2LMO = 0.76, and R2ex = 0.76). The present QSAR analysis identified that anti-BRD-4 activity is associated with structural characters such as the presence of saturated carbocyclic rings, the occurrence of carbon atoms near the center of mass of a molecule, and a specific combination of planer or aromatic nitrogen with ring carbon, donor, and acceptor atoms. The outcomes of the present analysis are also supported by X-ray-resolved crystal structures of compounds with BRD-4. Thus, the QSAR model effectively captured salient as well as unreported hidden pharmacophoric features. Therefore, the present study successfully identified valuable novel pharmacophoric features, which could be beneficial for the future optimization of lead/hit compounds for anti-BRD-4 activity.

Estrogen Receptor Alpha Binders for Hormone-Dependent Forms of Breast Cancer: e-QSAR and Molecular Docking Supported by X-ray Resolved Structures

“…We sequentially performed the following steps to build a widely applicable and thriving QSAR model for ER-α binding activity: 43,44 3). Thus, in this work, we adhered to the OECD-recommended guidelines for deriving a QSAR model for ER-α binding activity.…”

“…We sequentially performed the following steps to build a widely applicable and thriving QSAR model for ER-α binding activity: , (a) collection and curation of the data, (b) generation of 3D structures and calculation of molecular descriptors, (c) conducted objective feature selection (OFS), (d) split the data set into training (80%) and external validation (20%) sets, (e) conduction of subjective feature selection (SFS), (f) building a regression model, and (g) validation of the developed model (see Figure ). Thus, in this work, we adhered to the OECD-recommended guidelines for deriving a QSAR model for ER-α binding activity.…”

Pharmacophore Synergism in Diverse Scaffold Clinches in Aurora Kinase B

“…In this work, we adhered to the OECD’s and other researchers’ suggested standards and recommendations [ 17 , 18 , 19 , 32 , 43 , 44 ] for a successful QSAR analysis. The various procedures for creating a model included meticulous dataset selection, data curation, 3D structure production for all molecules, computation and trimming of molecular descriptors, model creation and extensive validation, and mechanistic interpretation [ 45 , 46 ]. To eliminate bias and ensure proper model validation, these stages were carried out one at a time.…”

“…To prevent over- and underfitting, the QSAR model must have an ideal number of molecular descriptors (variables). Consequently, the ideal number of descriptors for the model was identified using a straightforward graphical (or breaking point) method [ 45 , 46 , 52 ]. The value of Q2LOO typically increases considerably when a new variable (molecular descriptor) is added in stages to an MLR model until the desired elevation is reached.…”

“…Different combinations of various molecular descriptors were eventually found during the search for seven molecular descriptors for the QSAR model using GA–MLR. However, due to the statistical performance and the satisfaction of adhering to strict parameters and criteria, which have been recommended [ 17 , 18 , 19 , 23 , 27 , 32 , 33 , 44 , 45 , 46 , 52 , 53 , 54 , 55 , 56 , 57 ] by a significant number of researchers, only one combination of molecular descriptors was chosen. The following threshold values and conditions were used to select the model:…”