Free Energy-Based Methods to Understand Drug Resistance Mutations

  • Elvis A. F. Martis
  • Evans C. CoutinhoEmail author
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 27)


In this chapter, we present an overview of various computational methods, particularly, those that are used to compute the free energy of binding to understand target site mutations that will enable us to foresee mutations that could significantly affect drug binding. We begin by looking at the driving forces that lead to drug resistance and throw some light on the various mechanisms by which drugs can be rendered ineffective. Next, we studied molecular dynamic simulations and its use to understand the thermodynamics of protein–ligand interactions. Building on these fundamentals, we discuss various methods that are available to compute the free energy binding, their mathematical formulations, the practical aspects of each these methods and finally their use in understanding drug resistance.


Molecular dynamics Drug resistance MM-PB(GB)-SA Free energy perturbation Linear interaction energy Computational mutational scanning Thermodynamic integration 



E. A. F. Martis and E. C. Coutinho are grateful to Ian R. Craig, Ph.D. (BASF, Ludwigshafen) for his critical comments and feedback on this chapter. The authors are grateful to Department of Science and Technology (DST), Department of Biotechnology (DBT) and Council of Scientific and Industrial Research (CSIR) for their financial support to build the High-Performance Computing system at the Department of Pharmaceutical Chemistry, Bombay College of Pharmacy. E. A. F. Martis and E. C. Coutinho are also thankful to nVIDIA Corporation for their hardware support grant. E. A. F. Martis is indebted to BASF, Ludwigshafen, Germany for the Ph.D. fellowship and the MCBR4 (2015) consortium (Prof. Dr. P. Comba, University of Heidelberg; Prof. Dr H. Zipse LMU, Munich and Prof. Dr. G. N. Sastry, IICT, Hyderabad for MCBR visiting fellowship to Heine-Heinrich University of Düsseldorf, Germany). E. A. F. Martis would also like to thank Prof. Dr. Holger Gohlke, Heine-Heinrich University of Düsseldorf for his guidance during the sabbatical in his CPCLab. Gratitude is expressed to Sandhya Subash, Ph.D. (Bristol-Meyer-Squibb, India), for her assistance in preparing and proofreading the drafts of this manuscript.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Molecular Simulations Group, Department of Pharmaceutical ChemistryBombay College of PharmacyMumbaiIndia

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