A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations

Ni Made Pitri Susanti,Rahmana Emran Kartasasmita,Sophi Damayanti,Daryono Hadi Tjahjono

doi:10.3390/ijms222413423

Ni Made Pitri Susanti, Rahmana Emran Kartasasmita + Show 2 more

Open Access

https://doi.org/10.3390/ijms222413423

Copy DOI

Abstract

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.

Highlights

Accepted: 12 December 2021Cyclin-dependent kinases (CDKs) serve as the cell cycle’s main activators through phosphorylation of retinoblastoma (Rb) proteins as their key substrates
The results suggested that the interaction of palbociclib and all the hit compounds do not have different effects on Cyclin-Dependent Kinase 4 (CDK4) stability
Abemaciclib were extracted from the X-ray crystallography structure of Cyclin-Dependent Kinase 6 (CDK6)

Summary

Introduction

Accepted: 12 December 2021Cyclin-dependent kinases (CDKs) serve as the cell cycle’s main activators through phosphorylation of retinoblastoma (Rb) proteins as their key substrates. The activities of CDKs are tightly regulated by their cyclin catalytic subunit, as well as endogenous CDK inhibitors (CKI) with the ability to negatively regulate these activities. Cooperation between cyclin, CDK, and CKI is essential to ensure proper cell cycle progression [1,2]. Uncontrolled cell proliferation due to cell cycle dysregulation tends to cause subsequent cancer development, where increased expression of CDK or cyclin, as well as decreased levels of endogenous CKI, are commonly observed [3,4]. The most common type of breast cancer is the hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR+ /HER2− -) breast cancer, where CCND1 as an encoding of cyclin D1, the catalytic subunit of CDK4 and CDK6, is profoundly expressed [5,6,7]

Objectives

Results

Conclusion