Improvement in predicting drug sensitivity changes associated with protein mutations using a molecular dynamics based alchemical mutation method.

Publication date: Feb 07, 2020

While molecular-targeted drugs have demonstrated strong therapeutic efficacy against diverse diseases such as cancer and infection, the appearance of drug resistance associated with genetic variations in individual patients or pathogens has severely limited their clinical efficacy. Therefore, precision medicine approaches based on the personal genomic background provide promising strategies to enhance the effectiveness of molecular-targeted therapies. However, identifying drug resistance mutations in individuals by combining DNA sequencing and in vitro analyses is generally time consuming and costly. In contrast, in silico computation of protein-drug binding free energies allows for the rapid prediction of drug sensitivity changes associated with specific genetic mutations. Although conventional alchemical free energy computation methods have been used to quantify mutation-induced drug sensitivity changes in some protein targets, these methods are often adversely affected by free energy convergence. In this paper, we demonstrate significant improvements in prediction performance and free energy convergence by employing an alchemical mutation protocol, MutationFEP, which directly estimates binding free energy differences associated with protein mutations in three types of a protein and drug system. The superior performance of MutationFEP appears to be attributable to its more-moderate perturbation scheme. Therefore, this study provides a deeper level of insight into computer-assisted precision medicine.

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Ono, F., Chiba, S., Isaka, Y., Matsumoto, S., Ma, B., Katayama, R., Araki, M., and Okuno, Y. Improvement in predicting drug sensitivity changes associated with protein mutations using a molecular dynamics based alchemical mutation method. 06303. 2020 Sci Rep (10):1.

Concepts Keywords
Alchemical Medicinal chemistry
Convergence Drug resistance
Drug Resistance Resistance mutation
Free Energy Mutation
Genetic Branches of biology
Genetic Mutations Medical specialties
Infection Medicine
Molecular Dynamics
Precision Medicine
Targeted Therapies


Type Source Name
disease MESH cancer
disease MESH infection
drug DRUGBANK Coenzyme M
drug DRUGBANK Huperzine B
disease MESH lymphoma
drug DRUGBANK L-Tyrosine
drug DRUGBANK Alectinib
drug DRUGBANK Oseltamivir
disease MESH drug interactions
drug DRUGBANK Fidarestat
drug DRUGBANK Amber
drug DRUGBANK Water
drug DRUGBANK Sodium Chloride
disease MESH point mutations
drug DRUGBANK Gold
drug DRUGBANK Ademetionine
disease MESH dissociation
drug DRUGBANK Amino acids
disease MESH insertion mutations
drug DRUGBANK Proline
drug DRUGBANK L-Cysteine
drug DRUGBANK Aspartame
disease MESH Pathology
drug DRUGBANK Platinum
drug DRUGBANK Bedaquiline
drug DRUGBANK Amprenavir
drug DRUGBANK Vandetanib
drug DRUGBANK Laninamivir octanoate
disease MESH influenza
drug DRUGBANK Diethylstilbestrol
drug DRUGBANK Lauric Acid
drug DRUGBANK Gefitinib


Original Article

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