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.
References
1. Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson B, Mitsuya H, Erickson JW (1995) Kinetic
characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug
pressure. Biochem 34(29):9282–9287
2. Schliekelman P, Garner C, Slatkin M (2001) Natural selection and resistance to HIV. Nature
411(6837):545–546
3. Toprak E, Veres A, Michel J-B, Chait R, Hartl DL, Kishony R (2012) Evolutionary paths to
antibiotic resistance under dynamically sustained drug selection. Nature Genet 44(1):101–
105
4. Yang Z, Nielsen R, Goldman N, Pedersen A-MK (2000) Codon-substitution models for
heterogeneous selection pressure at amino acid sites. Genetics 155(1):431–449
5. Blanchard JS (1996) Molecular mechanisms of drug resistance in Mycobacterium
tuberculosis. Annu Rev Biochem 65(1):215–239
6. Borst P, Ouellette M (1995) New mechanisms of drug resistance in parasitic protozoa. Annu
Rev Microbiol 49(1):427–460
7. Longley D, Johnston P (2005) Molecular mechanisms of drug resistance. J Pathol 205
(2):275–292
8. Walsh C (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature
406:775–781
9. Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin
Microbiol 2(5):489–493
10. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ (2006) The
competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–
1946
11. Böttger EC, Springer B, Pletschette M, Sander P (1998) Fitness of antibiotic-resistant
microorganisms and compensatory mutations. Nature Med 4(12):1343–1344
12. Sander P, Springer B, Prammananan T, Sturmfels A, Kappler M, Pletschette M, Böttger EC
(2002) Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob
Agents Chemother 46(5):1204–1211
13. Cao ZW, Han LY, Zheng CJ, Ji ZL, Chen X, Lin HH, Chen YZ (2005) Computer prediction
of drug resistance mutations in proteins. Drug Discov Today 10(7):521–529
14. Rhee S-Y, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW (2003) Human
immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids
Res 31(1):298–303
15. Shafer RW (2006) Rationale and uses of a public HIV drug-resistance database. J Infect Dis
194(Supplement 1):S51–S58
16. Kumar R, Chaudhary K, Gupta S, Singh H, Kumar S, Gautam A, Kapoor P, Raghava GP
(2013) CancerDR: cancer drug resistance database. Sci Rep 3:1445
17. Sandgren A, Strong M, Muthukrishnan P, Weiner BK, Church GM, Murray MB (2009)
Tuberculosis drug resistance mutation database. PLoS Med 6(2):e1000002
Free Energy-Based Methods to Understand Drug Resistance Mutations
19
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.
References
1. Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson B, Mitsuya H, Erickson JW (1995) Kinetic
characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug
pressure. Biochem 34(29):9282–9287
2. Schliekelman P, Garner C, Slatkin M (2001) Natural selection and resistance to HIV. Nature
411(6837):545–546
3. Toprak E, Veres A, Michel J-B, Chait R, Hartl DL, Kishony R (2012) Evolutionary paths to
antibiotic resistance under dynamically sustained drug selection. Nature Genet 44(1):101–
105
4. Yang Z, Nielsen R, Goldman N, Pedersen A-MK (2000) Codon-substitution models for
heterogeneous selection pressure at amino acid sites. Genetics 155(1):431–449
5. Blanchard JS (1996) Molecular mechanisms of drug resistance in Mycobacterium
tuberculosis. Annu Rev Biochem 65(1):215–239
6. Borst P, Ouellette M (1995) New mechanisms of drug resistance in parasitic protozoa. Annu
Rev Microbiol 49(1):427–460
7. Longley D, Johnston P (2005) Molecular mechanisms of drug resistance. J Pathol 205
(2):275–292
8. Walsh C (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature
406:775–781
9. Andersson DI, Levin BR (1999) The biological cost of antibiotic resistance. Curr Opin
Microbiol 2(5):489–493
10. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ (2006) The
competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312:1944–
1946
11. Böttger EC, Springer B, Pletschette M, Sander P (1998) Fitness of antibiotic-resistant
microorganisms and compensatory mutations. Nature Med 4(12):1343–1344
12. Sander P, Springer B, Prammananan T, Sturmfels A, Kappler M, Pletschette M, Böttger EC
(2002) Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob
Agents Chemother 46(5):1204–1211
13. Cao ZW, Han LY, Zheng CJ, Ji ZL, Chen X, Lin HH, Chen YZ (2005) Computer prediction
of drug resistance mutations in proteins. Drug Discov Today 10(7):521–529
14. Rhee S-Y, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW (2003) Human
immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids
Res 31(1):298–303
15. Shafer RW (2006) Rationale and uses of a public HIV drug-resistance database. J Infect Dis
194(Supplement 1):S51–S58
16. Kumar R, Chaudhary K, Gupta S, Singh H, Kumar S, Gautam A, Kapoor P, Raghava GP
(2013) CancerDR: cancer drug resistance database. Sci Rep 3:1445
17. Sandgren A, Strong M, Muthukrishnan P, Weiner BK, Church GM, Murray MB (2009)
Tuberculosis drug resistance mutation database. PLoS Med 6(2):e1000002
Free Energy-Based Methods to Understand Drug Resistance Mutations
19