Investigating the Role of Missense SNPs on ALDH 1A1 mediated pharmacokinetic resistance to cyclophosphamide.

Abstract

Cyclophosphamide (CP) is a well-known anti-cancer drug, which exerts its therapeutic effect by DNA cross-linking, both within and between DNA strands. Earlier, a single dose of CP was enough for an effective treatment however due to overexpression of ALDH 1A1 in cancer cells and consequent drug inactivation, the quality of treatment suffered a lot. Drug inactivation via Drug Metabolizing Enzyme (DME) like Aldehyde dehydrogenase 1A1 (ALDH 1A1) is one of the resistance mechanism which is least considered and somewhat overlooked. The current study focused on investigating the impact of missense SNPs on ALDH 1A1 mediated pharmacokinetic resistance to CP. To achieve this aim, we selected 14 missense SNPs from the large pool of SNPs database. The stability of the mutants corresponding to selected SNPs was then determined using web-based tools like I-Mutant, CUPSAT, Maestro-web, STRUM, Eris, SDM, DUET, I-Stable. The obtained results from the mentioned web tools were later validated by molecular dynamic simulations. Furthermore, to find out the optimal range in terms of geometrical parameters and binding affinity for a molecule to be a good substrate for ALDH 1A1, some well-reported substrates of ALDH1A1 were pooled from the literature. Subsequently, similar parameters were calculated for each aldophosphamide (Active metabolite of CP) - mutant complexes to determine if these parameters lie within the optimal range. Based on this analyses population which is most or least susceptible to resistance was suggested. Our results demonstrated that the population group corresponding to rs11554423 (Gly125Arg) and rs763363983 (Val460Leu) mutation may be least vulnerable to CP resistance. Whereas, the population corresponding to rs1049981 (Asn121Ser) and rs774967243 (Val295Leu) SNPs may be most vulnerable to CP resistance.

• Authors: Himanshu Verma, Om Silakari
• Journal: Computers in biology and medicine (Comput Biol Med) Vol. 125 Pg. 103979 (10 2020) ISSN: 1879-0534 [Electronic] United States
• PMID: 32877739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Cyclophosphamide
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase
• Retinal Dehydrogenase

Topics

• Aldehyde Dehydrogenase (genetics)
• Aldehyde Dehydrogenase 1 Family
• Cyclophosphamide
• Polymorphism, Single Nucleotide (genetics)
• Retinal Dehydrogenase