Roles of Integration of Multiple Simulation Technologies in Insights into Binding Mechanism of Inhibitors to BRD Family

Shiliang Wu

doi:10.11648/j.abb.20210901.13

Abstract

Insights into binding mechanism of inhibitors to targets are expected to provide a meaningfully theoretical guidance for design and development of effective inhibitors inhibiting of the activity of targets. It is well known that the bromodomain (BRD) family has been thought as a promising target utilized for treating various human diseases, such as inflammatory disorders, malignant tumors, acute myelogenous leukemia (AML), bone diseases, etc. In this work, we summarize the roles of integration of multiple simulation technologies in exploring atomic-level dynamics changes of the BRD family because of inhibitor bindings. Molecular dynamics (MD) simulations, binding free energy calculations, calculations of dynamics cross-correlation maps (DCCMs), and principal component (PC) analysis are integrated together to uncover binding modes of inhibitors to BRDs. The results obtained from binding free energy calculations can measure binding ability of inhibitors to BRDs, and explore the main driving forces of the binding of inhibitors to BRDs. The information stemming from PC analysis can reveal the changes in conformations, internal dynamics and movement patterns of BRDs due to inhibitor associations. Residue-based free energy decomposition method is wielded to unveil contributions of separate residues to inhibitor bindings, and explore the decisive factors that affect the bindings of inhibitors to BRDs.

Highlights

With fast development of computer technology, multiple simulation technologies, such as molecular dynamics (MD) simulations, binding free energy predictions, principal component (PC) analysis, dynamics cross-correlation maps (DCCMs) and residue-based free energy decomposition, are play increasing roles in identification of hot spots of inhibitor-target bindings and drug design
Wang et al explored molecular mechanisms of inhibitor bindings to bromodomain-containing protein 4 (BRD4) using MD simulations and calculations of binding free energies, and the results demonstrate that the associations of inhibitors obviously affect the flexibility, conformational changes, motion modes, and internal dynamics of BRD4 (1), and show that residues Gln85, Val87, Leu92, Leu94, Cys136 and Ile146 produce the CH-π interactions with inhibitors, while the residues Trp81, Pro82, Phe83 and Tyr139 form the π-π interactions [1]
Su et al studied the selective mechanism of inhibitors toward BRD4, BRD7 and BRD9, and the results show that Ile164 and Asn211 in BRD7 and Ile53 and Asn100 in BRD9 play a significant role in the selectivity of inhibitor H1B to BRD7 and BRD9, in addition, several key residues Phe44, Ile53, Asn100, Thr104 in BRD9 and Pro82, Lys91, Asn140, Asp144 in BRD4 provide significant contributions to binding selectivity of inhibitors toward BRD9 and BRD4 [2]

Summary

Introduction

With fast development of computer technology, multiple simulation technologies, such as molecular dynamics (MD) simulations, binding free energy predictions, principal component (PC) analysis, dynamics cross-correlation maps (DCCMs) and residue-based free energy decomposition, are play increasing roles in identification of hot spots of inhibitor-target bindings and drug design. Su et al studied the selective mechanism of inhibitors toward BRD4, BRD7 and BRD9, and the results show that Ile164 and Asn211 in BRD7 and Ile and Asn100 in BRD9 play a significant role in the selectivity of inhibitor H1B to BRD7 and BRD9, in addition, several key residues Phe, Ile, Asn100, Thr104 in BRD9 and Pro, Lys, Asn140, Asp144 in BRD4 provide significant contributions to binding selectivity of inhibitors toward BRD9 and BRD4 [2]. The efficient integration of these simulation technologies will be of significance for design of potent inhibitors toward targets

Methods

Results

Conclusion