Rational Approach to New Chemical Entities with Antiproliferative Activity on Ab1 Tyrosine Kinase Encoded by the BCR-ABL Gene: An Hierarchical Biochemoinformatics Analysis

Vitor H da S Sanches; Cleison C Lobato; Luciane B Silva; Igor V F Dos Santos; Elcimar de S Barros; Alexandre de A Maciel; Elenilze F B Ferreira; Kauê S da Costa; José M Espejo-Román; Joaquín M C Rosa; Njogu M Kimani; Cleydson B R Santos

doi:10.3390/ph17111491

Rational Approach to New Chemical Entities with Antiproliferative Activity on Ab1 Tyrosine Kinase Encoded by the BCR-ABL Gene: An Hierarchical Biochemoinformatics Analysis

Pharmaceuticals (Basel). 2024 Nov 6;17(11):1491. doi: 10.3390/ph17111491.

Authors

Vitor H da S Sanches^{1

2

3}, Cleison C Lobato^{1

2

3}, Luciane B Silva^{1

2

3}, Igor V F Dos Santos^{1

3}, Elcimar de S Barros^{3

4}, Alexandre de A Maciel^{3

4}, Elenilze F B Ferreira^{3

4

5}, Kauê S da Costa⁶, José M Espejo-Román⁷, Joaquín M C Rosa⁷, Njogu M Kimani⁸, Cleydson B R Santos^{1

2

3

4}

Affiliations

¹ Biodiversity and Biotechnology Network of the Legal Amazon, Biotechnology Department, Federal University of Amapá, Macapá 68903-419, AP, Brazil.
² Graduate Program in Medicinal Chemistry and Molecular Modeling, Federal University of Pará, Belém 66075-110, PA, Brazil.
³ Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68903-419, AP, Brazil.
⁴ Graduate Program of Pharmaceutical Innovation, Federal University of Amapá, Macapá 68902-280, AP, Brazil.
⁵ Laboratory of Organic Chemistry and Biochemistry, University of the State of Amapá, Macapá 68900-070, AP, Brazil.
⁶ Computational Simulation Laboratory, Institute of Biodiversity, Federal University of Western Pará, Vera Paz Street, w/n Salé, Santarém 68040-255, PA, Brazil.
⁷ Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, University of Granada, 18071 Granada, Spain.
⁸ Natural Product Chemistry and Computational Drug Discovery Laboratory, Embu P.O. Box 6-60100, Kenya.

Abstract

Background: This study began with a search in three databases, totaling six libraries (ChemBridge-DIVERSet, ChemBridge-DIVERSet-EXP, Zinc_Drug Database, Zinc_Natural_Stock, Zinc_FDA_BindingDB, Maybridge) with approximately 2.5 million compounds with the aim of selecting potential inhibitors with antiproliferative activity on the chimeric tyrosine kinase encoded by the BCR-ABL gene. Methods: Through hierarchical biochemoinformatics, ADME/Tox analyses, biological activity prediction, molecular docking simulations, synthetic accessibility and theoretical synthetic routes of promising compounds and their lipophilicity and water solubility were realized. Results: Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the top100/base (600 structures), in comparison with the commercial drug imatinib, showed that only nine exhibited the desired properties. In the prediction of biological activity, the results of the nine selected structures ranged from 13.7% < Pa < 65.8%, showing them to be potential protein kinase inhibitors. In the molecular docking simulations, the promising molecules LMQC01 and LMQC04 showed significant values in molecular targeting (PDB 1IEP-resolution 2.10 Å). LMQC04 presented better binding affinity (∆G = -12.2 kcal mol^-1 with a variation of ±3.6 kcal mol^-1) in relation to LMQC01. The LMQC01 and LMQC04 molecules were advanced for molecular dynamics (MD) simulation followed by Molecular Mechanics with generalized Born and Surface Area solvation (MM-GBSA); the comparable, low and stable RMSD and ΔE values for the protein and ligand in each complex suggest that the selected compounds form a stable complex with the Abl kinase domain. This stability is a positive indicator that LMQC01 and LMQC04 can potentially inhibit enzyme function. Synthetic accessibility (SA) analysis performed on the AMBIT and SwissADME webservers showed that LMQC01 and LMQC04 can be considered easy to synthesize. Our in silico results show that these molecules could be potent protein kinase inhibitors with potential antiproliferative activity on tyrosine kinase encoded by the BCR-ABL gene. Conclusions: In conclusion, the results suggest that these ligands, particularly LMQC04, may bind strongly to the studied target and may have appropriate ADME/Tox properties in experimental studies. Considering future in vitro or in vivo assays, we elaborated the theoretical synthetic routes of the promising compounds identified in the present study. Based on our in silico findings, the selected ligands show promise for future studies in developing chronic myeloid leukemia treatments.

Keywords: binding affinity; chronic myeloid leukemia; drug design; imatinib; molecular docking.

Grants and funding

The authors gratefully acknowledge the financial support provided from Biodiversity and Biotechnology Network of the Legal Amazon (Rede Bionorte) and PROPESP/UFPA. Computational support of the Laboratory of Modeling and Computational Chemistry (LMQC) linked to the Department of Biological Sciences at Federal University of Amapá (UNIFAP/Macapá-Brazil), to the Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute at Federal University of Pará (UFPA/Belém-Brazil), University of the State of Amapá (UEAP) and Department of Pharmaceutical and Organic Chemistry—Institute of Biosanitary Research ibs.GRANADA—University of Granada (UGR-Granada-Spain).