A Virtual Screening Approach for the Identification of High Affinity Small Molecules Targeting BCR-ABL1 Inhibitors for the Treatment of Chronic Myeloid Leukemia

Abstract

CML originates due to reciprocal translocation in Philadelphia chromosome leading to the formation of fusion product BCR-ABL which constitutively activates tyrosine kinase signaling pathways eventually leading to abnormal proliferation of granulocytic cells. As a therapeutic strategy, BCR-ABL inhibitors have been clinically approved which terminates its phosphorylation activity and retards cancer progression. However, a number of patients develop resistance to inhibitors which demand for the discovery of new inhibitors. Given the drawbacks of present inhibitors, by high throughput virtual screening approaches, present study pursues to identify high affinity compounds targeting BCR-ABL1 anticipated to have safer pharmacological profiles. Five established BCR-ABL inhibitors formed the query compounds for identification of structurally similar compounds by Tanimoto coefficient based linear fingerprint search with a threshold of 95% against PubChemdatabase. Assisted by MolDock algorithm all compounds were docked against BCR-ABL protein in order to retrieve high affinity compounds. The parents and similars were further tested for their ADMET propertiesand bioactivity. Rebastinib formed higher affinity inhibitor than rest of the four established compound investigated in the study. Interestingly, Rebastinib similar compound with Pubchem ID: 67254402 was also shown to have highest affinity than other similars including the similars of respective five parents. In terms of ADMET properties Pubchem ID: 67254402 had appreciable ADMET profile and bioactivity. However, Rebastinib still stood as the best inhibitor in terms of binding affinity and ADMET properties than Pubchem ID: 67254402. Nevertheless, owing to the similar pharmacological properties with Rebastinib, Pubchem ID: 67254402 can be expected to form potential BCR-ABL inhibitor.

Design of PD-L1 inhibitors for lung cancer

“…Cavity one was observed to have the largest volume and the presence of the ligand and was hence chosen for docking of the prepared ligands. Docking procedure holding parameter of maximum iteration of 1500, grid solution 0.2 having a binding affinity, maximum population size 50, the protein and ligands were assessed on the subsequent confirmation of the Internal Electrostatic interaction (Internal ES), sp2-sp2 torsions, and internal hydrogen bond interaction [36-42]. The binding site outlined the first cavity according to high volume.…”

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

“…The admetSAR database with ADMET properties of a compound deal with its absorption, distribution, metabolism, excretion, and toxicity in the human body which play the key role in the discovery of a compound. Owing to the superior affinity of the best-established compound and virtual screened compound, the bioactivity properties and toxicity was predicted by using admetSAR (Shameer et al, 2017;Sharda et al, 2017;Sharma et al, 2018;Nayarisseri et al, 2019). The admetSAR database which constitutes the pharmacokinetic profile of a drug molecule is essential in evaluating its pharmacodynamic activities.…”

An In silico Approach to Identify High Affinity Small Molecule Targeting m-TOR Inhibitors for the Clinical Treatment of Breast Cancer

“…Targeted three-dimensional structural coordinates was pre-processed using Protein Preparation Wizard module in Schrödinger Suite (Protein preparation wizard, Schrodinger, 2017) (Sharda et al, 2017;Bandaru et al, 2017) by implying the parameters like assigning bond orders, zero-order bonds to metal atoms, selenomethionine to methionine conversion, filling absent hydrogen's, capping termini, side chains and loops, and removing waters beyond 5 Å distance surrounding the co-crystallized ligand (Bandaru et al, 2017;Shameer et al, 2017;Nasr et al, 2015;Khandekar et al, 2016;Singh et al, 2019). Further, tautomerization and protonation states were predicted in favor of ligand at pH 7.00.…”