Exploring the Prominent and Concealed Inhibitory Features for Cytoplasmic Isoforms of Hsp90 Using QSAR Analysis.

Magdi E A Zaki,Vijay H Masand,Vaishali M Patil,Mithilesh M Rathore,Sami A Al-Hussain,Sumer D Thakur,Syed Nasir Abbas Bukhari

doi:10.3390/ph15030303

Abstract

Cancer is a major life-threatening disease with a high mortality rate in many countries. Even though different therapies and options are available, patients generally prefer chemotherapy. However, serious side effects of anti-cancer drugs compel us to search for a safer drug. To achieve this target, Hsp90 (heat shock protein 90), which is responsible for stabilization of many oncoproteins in cancer cells, is a promising target for developing an anti-cancer drug. The QSAR (Quantitative Structure–Activity Relationship) could be useful to identify crucial pharmacophoric features to develop a Hsp90 inhibitor. Therefore, in the present work, a larger dataset encompassing 1141 diverse compounds was used to develop a multi-linear QSAR model with a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The new developed six-parameter model satisfies the recommended values for a good number of validation parameters such as R2tr = 0.78, Q2LMO = 0.77, R2ex = 0.78, and CCCex = 0.88. The present analysis reveals that the Hsp90 inhibitory activity is correlated with different types of nitrogen atoms and other hidden structural features such as the presence of hydrophobic ring/aromatic carbon atoms within a specific distance from the center of mass of the molecule, etc. Thus, the model successfully identified a variety of reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with Hsp90.

Highlights

Cancer kills; medicinal chemists are continuously trying to develop therapeutic agents that could retard the growth of cancer cells
The exhaustive and heuristic search resulted in the development of a six-descriptorbased QSAR model, which was subjected to thorough statistical validation for internal and external validations
The earlier work identified the role of amide group, and in the present work, we successfully identified that a combination of amide group with H-bond donor/acceptor within six bonds is a better strategy to have better Hsp90 inhibitory activity

Summary

Introduction

Cancer kills; medicinal chemists are continuously trying to develop therapeutic agents that could retard the growth of cancer cells. (heat shock protein 90, known as HSPC) is overexpressed [1]. It is a highly conserved, non-fibrous, and chaperone protein with a key role in many cellular processes like proper folding of other proteins, apoptosis, cell cycle control, cell viability, and degradation and signaling events [1–6]. Hsp (heat shock proteins) shield cells when stressed by higher temperatures. The number “90” comes from the fact that it weighs about. 90 kDa. There are two isoforms of Hsp: Hsp90α (the inducible form) and Hsp90β (the constitutive form), which are found in cytoplasm and share 85% sequence identity [1–6]

Methods

Results

Discussion

Conclusion