Monte Carlo Optimization-Based QSAR Study of Some Indole-Based Mcl-1 Inhibitors

Introduction

Apoptosis, also known as the ‘programmed cell death’, acts implicitly to remove the damaged or dangerous cells and maintain the normal homeostasis in the human body (Goldar et al., 2015; Elmore, 2007; Hassan et al., 2014). In cancerous cells, the overexpression of the inhibitors of apoptosis or deficiency of initiators of apoptosis also results in a decreased sensitivity of malignant cells to traditional cancer chemotherapy. The dysregulation or compromised regulation of apoptosis directly promotes tumorigenesis and drug resistance to different chemotherapeutic agents as well as targeted therapies (Mohammad et al., 2015; Mailloux et al., 2001; Li et al., 2017; Hanahan and Weinberg, 2011). Therefore, it is of great interest to the researchers to develop some small molecule inhibitors that can aid in the process of apoptosis of the necrotic cells. These inhibitors will be very useful for the treatment of haematological as well as diverse types of solid cancers (Huang et al., 2018; Pistritto et al., 2016).

A critical regulator of cellular apoptosis is the B-cell lymphoma protein 2 (BCL2). These are the family members of large structurally related proteins that can be pro-apoptotic or anti-apoptotic in nature (Kelly and Strasser, 2020). The dynamic balance between anti-apoptotic members (BCL-XL, BCL-W, Mcl-1) and pro-apoptotic members (BH3-only proteins like BIM, BAD, BID, PUMA, NOXA) can determine lifespan of a cell (Adams et al., 2007; Fletcher et al., 2019; Amin et al., 2020).The initiation of this pathway takes place under stress conditions resulted from various factors like deprivation of several growth factors, activation of different oncogenes or treatment with diverse chemotherapeutic drugs (Kelly and Strasser, 2020). As a result of this, initiator proteins bind to pro-apoptotic family members, resulted in activation of effector proteins BAK/ BAX complex. It further permeabilizes cytoplasmic mitochondria, resulting in depolarization and caspase activation, leading to apoptosis. In response to stress, normal cells upregulate proapoptotic family members to encourage apoptosis. In contrast, malignant cells elevate the expression of anti-apoptotic members like Mcl-1 that keeps pro-apoptotic members in check. This prevents cancer cells from eliciting apoptotic response (Czabotar et al., 2014).

Among all the members of BCL-2 family proteins, the one in which the researchers have become greatly interested in nowadays is myeloid cell leukemia 1 (Mcl-1) protein (Senichkin et al., 2019). This is perhaps the most abundant protein found to be present in different types of human cancers comprising acute myeloid leukemia, acute lymphocytic leukemia as well as different types of solid cancer. The expression of this protein is well regulated by the various signal transduction mechanisms P13K/AKT, p38 MAPK, JAK/STAT and so on (Amin et al., 2020). Investigation revealed that this protein is of particular interest as a cancer drug target due to the fact that the survival of carcinogenic cells can be restrained by the development of small molecule compounds that act as inhibitors of Mcl-1 protein.

Indole type derivatives are promising inhibitors of Mcl-1. In the current study, we have used Monte Carlo based classification QSAR study on certain indole based Mcl-1 inhibitors. The study points out useful structural fingerprints critical for the lead optimization of this type of derivatives for Mcl-1 inhibition. The present study as well as our previous study (Amin et al., 2020) will be helpful to the researchers for the development of indole based Mcl-1 inhibitors.