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90. Shirts MR, Mobley DL, Chodera JD (2007) Alchemical free energy calculations: ready for
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91. Wang Q, Edupuganti R, Tavares CD, Dalby KN, Ren P (2015) Using docking and
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and prioritizing the compound synthesis. Front Mol Biosci 2:9
92. Massova I, Kollman PA (1999) Computational alanine scanning to probe protein-protein
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93. Chellappan S, Kairys V, Fernandes MX, Schiffer C, Gilson MK (2007) Evaluation of the
substrate envelope hypothesis for inhibitors of HIV-1 protease. Proteins Struct Funct Bioinf
68(2):561–567
94. Nalam MN, Ali A, Altman MD, Reddy GKK, Chellappan S, Kairys V, Özen A, Cao H,
Gilson MK, Tidor B (2010) Evaluating the substrate-envelope hypothesis: structural analysis
of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol 84
(10):5368–5378
95. Shen Y, Altman MD, Ali A, Nalam MN, Cao H, Rana TM, Schiffer CA, Tidor B (2013)
Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem
Biol 8(11):2433–2441
96. Chellappan S, Kiran Kumar Reddy G, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V,
Fernandes MX, Altman MD, Tidor B (2007). Design of mutation‐resistant HIV protease
inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 69(5): 298–313
97. Kairys V, Gilson MK, Lather V, Schiffer CA, Fernandes MX (2009) Toward the design of
mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis. Chem Biol Drug Des 74(3):234–245
98. Nalam MN, Ali A, Reddy GKK, Cao H, Anjum SG, Altman MD, Yilmaz NK, Tidor B,
Rana TM, Schiffer CA (2013) Substrate envelope-designed potent HIV-1 protease inhibitors
to avoid drug resistance. Chem Biol 20(9):1116–1124
99. Nalam MN, Schiffer CA (2008) New approaches to HIV protease inhibitor drug design II:
testing the substrate envelope hypothesis to avoid drug resistance and discover robust
inhibitors. Curr Opin HIV AIDS 3(6):642
Free Energy-Based Methods to Understand Drug Resistance Mutations
23
simulations. J Phys Chem 94(21):8021–8024
81. Wang W, Wang J, Kollman PA (1999) What determines the van der waals coefficient b in
the LIE (linear interaction energy) method to estimate binding free energies using molecular
dynamics simulations? Proteins Struct Funct Bioinf 34(3):395–402
82. Bajorath J (2002) Integration of virtual and high-throughput screening. Nat Rev Drug
Discov 1(11):882–894
83. Shoichet BK (2004) Virtual screening of chemical libraries. Nature 432(7019):862–865
84. Zwanzig RW (1954) High-temperature equation of state by a perturbation method. i.
nonpolar gases. J Chem Phy 22(8):1420–1426
85. Zwanzig RW (1955) High-temperature equation of state by a perturbation method. II. polar
gases. J Chem Phy 23(10):1915–1922
86. van Gunsteren WF (1989) Methods for calculation of free energies and binding constants:
successes and problems. In: van Gunsteren WF, Weiner PK (eds) Computer simulation of
biomolecular systems: theoretical and experimental applications. Escom, Leiden, pp 27–59
87. van Gunsteren WF, Berendsen HJ (1987) Thermodynamic cycle integration by computer
simulation as a tool for obtaining free energy differences in molecular chemistry. J Comput
Aided Mol Des 1(2):171–176
88. Kollman P (1993) Free energy calculations: applications to chemical and biochemical
phenomena. Chem Rev 93(7):2395–2417
89. Chodera JD, Mobley DL, Shirts MR, Dixon RW, Branson K, Pande VS (2011) Alchemical
free energy methods for drug discovery: progress and challenges. Curr Opin Struct Biol 21
(2):150–160
90. Shirts MR, Mobley DL, Chodera JD (2007) Alchemical free energy calculations: ready for
prime time? Annu Rep Comput Chem D A Dixon 3:41–59
91. Wang Q, Edupuganti R, Tavares CD, Dalby KN, Ren P (2015) Using docking and
alchemical free energy approach to determine the binding mechanism of eEF2K inhibitors
and prioritizing the compound synthesis. Front Mol Biosci 2:9
92. Massova I, Kollman PA (1999) Computational alanine scanning to probe protein-protein
interactions: a novel approach to evaluate binding free energies. J Am Chem Soc 121
(36):8133–8143
93. Chellappan S, Kairys V, Fernandes MX, Schiffer C, Gilson MK (2007) Evaluation of the
substrate envelope hypothesis for inhibitors of HIV-1 protease. Proteins Struct Funct Bioinf
68(2):561–567
94. Nalam MN, Ali A, Altman MD, Reddy GKK, Chellappan S, Kairys V, Özen A, Cao H,
Gilson MK, Tidor B (2010) Evaluating the substrate-envelope hypothesis: structural analysis
of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol 84
(10):5368–5378
95. Shen Y, Altman MD, Ali A, Nalam MN, Cao H, Rana TM, Schiffer CA, Tidor B (2013)
Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem
Biol 8(11):2433–2441
96. Chellappan S, Kiran Kumar Reddy G, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V,
Fernandes MX, Altman MD, Tidor B (2007). Design of mutation‐resistant HIV protease
inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 69(5): 298–313
97. Kairys V, Gilson MK, Lather V, Schiffer CA, Fernandes MX (2009) Toward the design of
mutation-resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis. Chem Biol Drug Des 74(3):234–245
98. Nalam MN, Ali A, Reddy GKK, Cao H, Anjum SG, Altman MD, Yilmaz NK, Tidor B,
Rana TM, Schiffer CA (2013) Substrate envelope-designed potent HIV-1 protease inhibitors
to avoid drug resistance. Chem Biol 20(9):1116–1124
99. Nalam MN, Schiffer CA (2008) New approaches to HIV protease inhibitor drug design II:
testing the substrate envelope hypothesis to avoid drug resistance and discover robust
inhibitors. Curr Opin HIV AIDS 3(6):642
Free Energy-Based Methods to Understand Drug Resistance Mutations
23