Bioisosteric replacements of tyrosine kinases inhibitors to make potent and safe chemotherapy against malignant cells

Abstract

The liver function test is an imperative element in chemotherapy management due to the idiosyncratic reaction of chemotherapy drugs. This study primly aimed to replace the toxic fragments of known protein tyrosine kinases inhibitors (PTKi) to develop safe and effective chemotherapy. All the current PTKi’s were docked with the tyrosine kinases and metabolic enzymes to study the affinities on the target. It resulted from most of the PTKi’s found higher affinity and efficacy with metabolic enzymes lead the hepatic cells damage. To overcome this limitation of PTKi’s, a bioisosteric replacement strategy was achieved and conceptual analogs were designed. Specifically, the Generated pose of the Axitinib molecule showed that axitinib fragments C = C-, -C = O and NH₂ produced clashes with active site residues of tyrosine kinases protein and good affinity with metabolic enzyme primes to the liver toxicity. The above said fragments were replaced with various bioisosteric groups and efficacy was measured. The resulting molecule shows improved affinity with tyrosine kinases enzyme and less interactions with metabolic enzyme were imminent molecule for the treatment of malignant cells with outside effects.

Communicated by Ramaswamy H. Sarma

Keywords:

• PTKi’s
• chemotherapy
• SeeSAR
• hepatotoxicity
• tyrosine kinases

Acknowledgment

Thank you to the Biosolve IT, Germany, team for providing the free licenses (three months) to perform this research work. Also, thank you to Dr. T. Pattabhi Raman – Assistant Librarian, B.S. Abdur Rahman Crescent Institute of Science and Technology, Vandalur, Chennai, for the plagiarism check using Turnitin.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Authors’ contribution

NI and SB conceived and designed the study. NI and DM conducted the survey and collected the data. NI, SB and PA analyzed the data and wrote the article. NI, PA, and SB revised the manuscript critically. All authors approved the final version of the manuscript.