Proximicin A-C as prospective HER2-positive and negative breast cancer drugs: Molecular docking and in silico ADME modeling

Abstract

Breast cancer is the second leading cause of cancer-related death among women worldwide. Proximicin A-C are bioactive chemicals produced by the marine Verrucosispora strain, which have been shown to have potent cytostatic effect against human breast cancer [MCF 7]. HER2 (Human epidermal growth factor receptor 2) is a gene that has been linked to breast cancer development. The study’s goals are to (1) forecast the intensity of binding affinity and interactions between HER2 and proximicin A-C, and (2) analyze ADME characteristics of proximicin A-C (Absorption, Distribution, Metabolism, and Excretion). The CB-Dock web service was used to dock proximicin A-C and commonly used breast cancer medicines Neratinib (Nerlynx) and Talazoparib against HER2, and protein-ligand interaction findings were collected via the protein-ligand interaction profiler (PLP) web server. The SwissADME web server was used to investigate ADME properties of the substances. In terms of docking, proximicin A has a vina score of -8.6, proximicin B and C has a score of -10, Talazoparib has a vina score of -8.5, and Neratinib (Nerlynx) has a vina score of -10.2 on CB-Dock. This means that proximicin B and C bind to HER2 more strongly than proximicin A and Talazoparib. Furthermore, their high binding affinity is nearly equivalent to Neratinibs (Nerlynx). Talazoparib has a lower binding affinity for HER2 than proximicin A. With HER2, all three chemicals have a strong hydrogen bond and hydrophobic contact. SwissADME estimated that all three substances follow the Lipinski rule (RO5) and have a bioavailability score of 0.55. They don’t have any structural issue in medicinal chemistry (no alerts in PAINS and Brenk forecasts), and their synthetic accessibility scales range from 3 to 3.5. Only proximicin A, on the other hand, has the leadlikeness feature. All three drugs failed to cross the blood-brain barrier (BBB) in terms of pharmacokinetics. Proximicin A has a high absorption rate in the GI tract, whereas proximicin B-C has a low absorption rate in the GI tract (GI). Similarly, proximicin A is neither a P-gp substrate nor a CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 inhibitor. Proximicin B-C, on the other hand, are P-gp substrates, and proximicin C is an inhibitor of all provided CYP enzymes, whilst proximicin B inhibits only three. Overall, proximicin A-C could be used as a possible breast cancer therapeutic candidate. Proximicin B-C will outperform proximicin A in terms of therapeutic efficacy. Proximicin A, on the other hand, will have better ADME qualities than Proximicin B-C. This study will provide the lead information for developing a new breast cancer medication with a good pharmacological profile.