Analyzing Indole-fused benzooxazepines as inhibitors of apoptosis pathway-related proteins using multifaceted computational medicinal chemistry

Abstract

In this study, quantum chemical (QC) investigations, virtual screening, molecular docking, and molecular dynamics analysis of indole-fused benzooxazepines derivatives (IFBOs) are presented. The ab-initio density function theory (DFT) using Becke's three parameters hybrid functional (B3LYP) and Hartree-Fock (HF) with 6-311+G(d) level of theory were used to optimize IFBOs. The most suitable level is determined as DFT(B3LYP)6-311+G(d) by correlation of observed and calculated results of IFBOs (1-8). IR, NMR, quantum chemical descriptors, and frontier molecular orbitals (FMOs) were examined in detail. Similarly, virtual drug-likeness screening of IFBOs (1-8) was also performed including molecular descriptors (MDs) and bioactivity score (BS) along with absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were computed to reveal their biological activity. Moreover, their potential anticancer activity target was explored by molecular docking and molecular dynamics analyses. Mainly apoptosis pathway-related protein targets including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX and poly-ADP-ribose-polymerase-1 (PARP1) were studied to find the most prominent target of IFBOs to display their potential anticancer activity. As a result, IFBO-7 revealed the best molecular interaction profile with PARP1 and showed its potent inhibitory activity.