The Anticancer Activity for the Bumetanide-Based Analogs via Targeting the Tumor-Associated Membrane-Bound Human Carbonic Anhydrase-IX Enzyme

Abstract

The membrane-bound human carbonic anhydrase (hCA) IX is widely recognized as a marker of tumor hypoxia and a prognostic factor within several human cancers. Being undetected in most normal tissues, hCA-IX implies the pharmacotherapeutic advent of reduced off-target adverse effects. We assessed the potential anticancer activity of bumetanide-based analogues to inhibit the hCA-IX enzymatic activity and cell proliferation of two solid cancer cell lines, namely kidney carcinoma (A-498) and bladder squamous cell carcinoma (SCaBER). Bumetanide analogues efficiently inhibit the target hCA-IX in low nanomolar activity (IC50 = 4.4–23.7 nM) and have an excellent selectivity profile (SI = 14.5–804) relative to the ubiquitous hCA-II isoform. Additionally, molecular docking studies provided insights into the compounds’ structure–activity relationship and preferential binding of small-sized as well as selective bulky ligands towards the hCA-IX pocket. In particular, 2,4-dihydro-1,2,4-triazole-3-thione derivative 9c displayed pronounced hCA-IX inhibitory activity and impressive antiproliferative activity on oncogenic A-498 kidney carcinoma cells and is being considered as a promising anticancer candidate. Future studies will aim to optimize this compound to fine-tune its anticancer activity as well as explore its potential through in-vivo preclinical studies.

Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

“…All ligands were constructed via the MOE2019.01 (Chemical Computing Group TM , Quebec, Canada) builder tool and subsequently energy-minimized utilizing the MMFF partial charges and MMFF (modified) force field as being implemented with 2000 steps of conjugate-gradient method till a gradient of 1 × 10 −3 Kcal/Å was reached [ 64 , 65 , 66 ]. Obtained ligand structures were saved in molecular database chemical file for incorporation within the molecular docking investigation.…”

Repurposing of Sitagliptin- Melittin Optimized Nanoformula against SARS-CoV-2; Antiviral Screening and Molecular Docking Studies

“…Using the Molecular Operating Environment (MOE; 2019) software program was deemed beneficial for conducting the presented molecular docking studies. This comprehensive platform permits construction of the investigated ligands, preparation of the biological target, carrying out of molecular docking simulation, and analysis of the predicted ligand-target interactions [ 52 ]. Moreover, the MOE software has multi-disciplinary applications including small Protein-Protein Docking protocol [ 53 , 54 ].…”

Design, Synthesis, Anticancer Activity, and Solid Lipid Nanoparticle Formulation of Indole- and Benzimidazole-Based Compounds as Pro-Apoptotic Agents Targeting Bcl-2 Protein

“…Molecular docking experiments were performed on the 14 investigated using Molecular Operating Environment (MOE) software as reported in previous work with few modifications [ 81 , 82 , 83 ]. In brief, ligands were constructed via the MOE “builder” tool, and then proceeded through the minimization step, adopting MMFF94x forcefield and 2000 steps of conjugate-gradient approach till a gradient of 0.001 Kcal/Å was reached 0.1 RMS Kcal/mol/Å 2 .…”