*Result*: A Robust Ensemble Machine Learning Approach for Inhibitor Discovery: Case Study of HIV-1 NNRTI and Validation Using MD Simulation.
Title:
A Robust Ensemble Machine Learning Approach for Inhibitor Discovery: Case Study of HIV-1 NNRTI and Validation Using MD Simulation.
Authors:
Shree A; Physical and Biomolecular Research Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Ganjam, Odisha, 760010, India., Pani P; Physical and Biomolecular Research Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Ganjam, Odisha, 760010, India.; Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Ganjam, Odisha, 760010, India., Rana MK; Physical and Biomolecular Research Lab, Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Berhampur, Ganjam, Odisha, 760010, India.
Source:
Chemistry, an Asian journal [Chem Asian J] 2026 Jan; Vol. 21 (1), pp. e70340. Date of Electronic Publication: 2025 Sep 29.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 101294643 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1861-471X (Electronic) Linking ISSN: 1861471X NLM ISO Abbreviation: Chem Asian J Subsets: MEDLINE
Imprint Name(s):
Original Publication: Weinheim, Germany : Wiley-VCH, c2006-
MeSH Terms:
HIV Reverse Transcriptase*/antagonists & inhibitors , HIV Reverse Transcriptase*/metabolism , Reverse Transcriptase Inhibitors*/chemistry , Reverse Transcriptase Inhibitors*/pharmacology , HIV-1*/enzymology , HIV-1*/drug effects , Anti-HIV Agents*/chemistry , Anti-HIV Agents*/pharmacology , Machine Learning* , Molecular Dynamics Simulation* , Drug Discovery*, Humans ; Molecular Docking Simulation ; Molecular Structure
References:
F. Barré‐Sinoussi, J. C. Chermann, F. Rey, M. T. Nugeyre, S. Chamaret, J. Gruest, C. Dauguet, C. Axler‐Blin, F. Vézinet‐Brun, C. Rouzioux, W. Rozenbaum, L. Montagnier, Science 1983, 220, 868–871.
D. C. Douek, M. Roederer, R. A. Koup, Annu. Rev. Med. 2009, 60, 471–484.
M. K. Powell, K. Benková, P. Selinger, M. Dogoši, I. Kinkorová Luňáčková, H. Koutníková, J. Laštíková, A. Roubíčková, Z. Špůrková, L. Laclová, V. Eis, J. Šach, P. Heneberg, PLoS One 2016, 11, e0162704.
R. W. Shafer, D. A. Vuitton, Biomed. Pharmacother. 1999, 53, 73–86.
W.‐S. Hu, S. H. Hughes, Cold Spring Harbor Perspect. Med. 2012, 2, a006882.
G. Li, Y. Wang, E. De Clercq, Acta Pharm. Sin. B 2022, 12, 1567–1590.
S. G. Sarafianos, B. Marchand, K. Das, D. M. Himmel, M. A. Parniak, S. H. Hughes, E. Arnold, J. Mol. Biol. 2009, 385, 693–713.
J. F. Davies, Z. Hostomska, Z. Hostomsky, S. R. Jordan, D. A. Matthews, Science 1991, 252, 88–95.
B. A. Larder, D. J. M. Purifoy, K. L. Powell, G. Darby, Nature 1987, 327, 716–717.
M. M. Lightfoote, J. E. Coligan, T. M. Folks, A. S. Fauci, M. A. Martin, S. Venkatesan, J. Virol. 1986, 60, 771–775.
D. H. Ashley, M. Subhra, P. P. Kumar, J. D. Christopher, Curr. HIV Res. 2017, 15, 411–421.
a) E. Cichero, S. Cesarini, P. Fossa, A. Spallarossa, L. Mosti, Eur. J. Med. Chem. 2009, 44, 2059–2070;.
b) L. A. Kohlstaedt, J. Wang, J. M. Friedman, P. A. Rice, T. A. Steitz, Science 1992, 256, 1783–1790.
a) N. Sluis‐Cremer, Viruses, 6, 2014, 2960–2973;.
b) P. L. Boyer, M. J. Currens, J. B. McMahon, M. R. Boyd, S. H. Hughes, J. Virol. 1993, 67, 2412–2420.
S. Bertagnolio, L. Hermans, M. R. Jordan, S. Avila‐Rios, C. Iwuji, A. Derache, E. Delaporte, A. Wensing, T. Aves, A. S. M. Borhan, A. Leenus, N. Parkin, M. Doherty, S. Inzaule, L. Mbuagbaw, J. Infect. Dis. 2021, 224, 377–388.
A. Kwara, G. Ramachandran, S. Swaminathan, Expert Opin. Drug Metab. Toxicol. 2010, 6, 55–68.
a) A. Singh, Artif. Intell. Chem. 2024, 2, 100071;.
b) A. Blanco‐González, A. Cabezón, A. Seco‐González, D. Conde‐Torres, P. Antelo‐Riveiro, Á. Piñeiro, R. Garcia‐Fandino, Pharmaceuticals 2023, 16, 891.
a) M. C. Steiner, K. M. Gibson, K. A. Crandall, Viruses, 12, 2020;.
b) L. Blassel, A. Tostevin, C. J. Villabona‐Arenas, M. Peeters, S. Hué, O. Gascuel, PLoS Comput. Biol. 2021, 17, e1008873.
N. Kumar, V. Acharya, Comput. Biol. Med. 2023, 153, 106525.
a) L. A. Machado, E. Krempser, A. C. R. Guimarães, Front. Drug Discov. 2022, 2, 954911;.
b) J. Zhou, J. Hao, L. Peng, H. Duan, Q. Luo, H. Yan, H. Wan, Y. Hu, L. Liang, Z. Xie, W. Liu, G. Zhao, J. Hu, Comput. Math. Methods Med. 2021, 2021, 5559338;.
c) A. K. Gao, T. B. Chen, V. L. Kouznetsova, I. F. Tsigelny, Artif. Intell. Chem. 2023, 1, 100014.
M. Néstor, C.‐R. Tania, M. Ophir, G.‐P. James, Inform. Med. Unlocked 2024, 48, 101512.
a) I. P. Singh, S. Bharate, K. Bhutani, Curr. Sci. 2005, 89, 269–290;.
b) S. S. Yang, G. M. Cragg, D. J. Newman, J. P. Bader, J. Nat. Prod. 2001, 64, 265–277.
B. F. Darst, K. C. Malecki, C. D. Engelman, BMC Genet. 2018, 19, 65.
H. Moriwaki, Y.‐S. Tian, N. Kawashita, T. Takagi, J. Cheminform. 2018, 10, 4.
Q. Zhang, P. Liu, X. Wang, Y. Zhang, Y. Han, B. Yu, Appl. Soft Comput. 2021, 99, 106921.
L. Fu, S. Shi, J. Yi, N. Wang, Y. He, Z. Wu, J. Peng, Y. Deng, W. Wang, C. Wu, A. Lyu, X. Zeng, W. Zhao, T. Hou, D. Cao, Nucleic Acids Res. 2024, 52, W422–W431.
a) A. Lavecchia, R. Costi, M. Artico, G. Miele, E. Novellino, A. Bergamini, E. Crespan, G. Maga, R. Di Santo, ChemMedChem 2006, 1, 1379–1390;.
b) R. K. Rawal, Y. S. Prabhakar, S. B. Katti, E. De Clercq, Bioorg. Med. Chem. 2005, 13, 6771–6776.
N. G. Sharaf, R. Ishima, A. M. Gronenborn, Biochemistry 2016, 55, 3864–3873.
I. Usach, V. Melis, J.‐E. Peris, J. Int. AIDS Soc. 2013, 16, 18567.
R. G. Huber, M. A. Margreiter, J. E. Fuchs, S. von Grafenstein, C. S. Tautermann, K. R. Liedl, T. Fox, J. Chem. Inf. Model. 2014, 54, 1371–1379.
A. Talukdar, B. Kundu, D. Sarkar, S. Goon, M. A. Mondal, Eur. J. Med. Chem. 2022, 236, 114304.
E. Sansinenea, F. Salazar, J. Jiménez, Á. Mendoza, A. Ortiz, Tetrahedron Lett. 2016, 57, 2604–2607.
H. Tse, Q. Gu, K.‐H. Sze, I. K. Chu, R. Y. T. Kao, K.‐C. Lee, C.‐W. Lam, D. Yang, S. S.‐C. Tai, Y. Ke, E. Chan, W.‐M. Chan, J. Dai, S.‐P. Leung, S.‐Y. Leung, K.‐Y. Yuen, J. Biol. Chem. 2017, 292, 19503–19520.
J. Ding, K. Das, C. Tantillo, W. Zhang, A. D. Clark, J.r., S. Jessen, X. Lu, Y. Hsiou, A. Jacobo‐Molina, K. Andries, R. Pauwels, H. Moereels, L. Koymans, P. A. J. Janssen, R. H. Smith J.r., M. K. Koepke, C. J. Michejda, S. H. Hughes, E. Arnold, Structure 1995, 3, 365–379.
R. Srivastava, S. K. Gupta, F. Naaz, P. S. Sen Gupta, M. Yadav, V. K. Singh, S. K. Panda, S. Biswal, M. K. Rana, S. K. Gupta, D. Schols, R. K. Singh, Comput. Biol. Chem. 2023, 106, 107910.
D. W. Wright, B. A. Hall, P. Kellam, P. V. Coveney, Biology 2012, 1, 222–244.
X. Gao, Z. Liu, W. Cui, L. Zhou, Y. Tian, Z. Zhou, PLoS One 2014, 9, e92357.
J. M. Seckler, K. J. Howard, M. D. Barkley, P. L. Wintrode, Biochemistry 2009, 48, 7646–7655.
D. Harris, R. Lee, H. S. Misra, P. K. Pandey, V. N. Pandey, Biochemistry 1998, 37, 5903–5908.
K. Das, J. D. Bauman, A. D. Clark, Y. V. Frenkel, P. J. Lewi, A. J. Shatkin, S. H. Hughes, E. Arnold, Proc. Natl. Acad. Sci. USA 2008, 105, 1466–1471.
S. K. Panda, P. S. Sen Gupta, S. Karmakar, S. Biswal, N. C. Mahanandia, M. K. Rana, J. Phys. Chem. Lett. 2023, 14, 10278–10284.
M. Rahimi, M. Taghdir, F. A. Joozdani, Sci. Rep. 2023, 13, 14179.
S. Tuske, J. Zheng, E. D. Olson, F. X. Ruiz, B. D. Pascal, A. Hoang, J. D. Bauman, K. Das, J. J. DeStefano, K. Musier‐Forsyth, P. R. Griffin, E. Arnold, Curr. Res. Struct. Biol. 2020, 2, 116–129.
G. G. Maisuradze, A. Liwo, H. A. Scheraga, J. Mol. Biol. 2009, 385, 312–329.
S. Genheden, U. Ryde, Expert Opin. Drug Discov. 2015, 10, 449‐461.
R. C. Bernardi, M. C. R. Melo, K. Schulten, Biochim. Biophys. Acta, Gen. Subj. 2015, 1850, 872‐877.
L. Shen, J. Shen, X. Luo, F. Cheng, Y. Xu, K. Chen, E. Arnold, J. Ding, H. Jiang, Biophys. J. 2003, 84, 3547–3563.
S.‐C. Nicolas, N. A. Temiz, B. Ivet, Curr. HIV Res. 2004, 2, 323–332.
B. Nizami, D. Sydow, G. Wolber, B. Honarparvar, Mol. BioSyst. 2016, 12, 3385–3395.
T. Cowen, K. Karim, S. Piletsky, Anal. Chim. Acta 2016, 936, 62–74.
a) I. Bahar, B. Erman, R. L. Jernigan, A. R. Atilgan, D. G. Covell, J. Mol. Biol. 1999, 285, 1023–1037;.
b) J. M. Seckler, M. D. Barkley, P. L. Wintrode, Biophys. J. 2011, 100, 144–153.
D. Yehorova, B. Di Geronimo, M. Robinson, P. M. Kasson, S. C. L. Kamerlin, Curr. Opin. Struct. Biol. 2024, 89, 102922.
S. Bowerman, J. Wereszczynski, in Methods in Enzymology, Vol. 578, (Ed: G. A. Voth), Academic Press, San Diego 2016, pp. 429–447.
H.‐T. Xu, M. Oliveira, E. L. Asahchop, M. McCallum, P. K. Quashie, Y. Han, Y. Quan, M. A. Wainberg, J. Virol. 2012, 86, 12983–12990.
a) J. Balzarini, J. Auwerx, F. Rodríguez‐Barrios, A. Chedad, V. Farkas, F. Ceccherini‐Silberstein, C. García‐Aparicio, S. Velázquez, E. De Clercq, C.‐F. Perno, M.‐J. Camarasa, F. Gago, Mol. Pharmacol. 2005, 68, 49;.
b) R. S. K. Vijayan, E. Arnold, K. Das, Proteins: Struct., Funct., Bioinf. 2014, 82, 815–829.
S.‐Y. Rhee, M. J. Gonzales, R. Kantor, B. J. Betts, J. Ravela, R. W. Shafer, Nucleic Acids Res. 2003, 31, 298–303.
E. Krissinel, K. Henrick, J. Mol. Biol. 2007, 372, 774–797.
D. C. Douek, M. Roederer, R. A. Koup, Annu. Rev. Med. 2009, 60, 471–484.
M. K. Powell, K. Benková, P. Selinger, M. Dogoši, I. Kinkorová Luňáčková, H. Koutníková, J. Laštíková, A. Roubíčková, Z. Špůrková, L. Laclová, V. Eis, J. Šach, P. Heneberg, PLoS One 2016, 11, e0162704.
R. W. Shafer, D. A. Vuitton, Biomed. Pharmacother. 1999, 53, 73–86.
W.‐S. Hu, S. H. Hughes, Cold Spring Harbor Perspect. Med. 2012, 2, a006882.
G. Li, Y. Wang, E. De Clercq, Acta Pharm. Sin. B 2022, 12, 1567–1590.
S. G. Sarafianos, B. Marchand, K. Das, D. M. Himmel, M. A. Parniak, S. H. Hughes, E. Arnold, J. Mol. Biol. 2009, 385, 693–713.
J. F. Davies, Z. Hostomska, Z. Hostomsky, S. R. Jordan, D. A. Matthews, Science 1991, 252, 88–95.
B. A. Larder, D. J. M. Purifoy, K. L. Powell, G. Darby, Nature 1987, 327, 716–717.
M. M. Lightfoote, J. E. Coligan, T. M. Folks, A. S. Fauci, M. A. Martin, S. Venkatesan, J. Virol. 1986, 60, 771–775.
D. H. Ashley, M. Subhra, P. P. Kumar, J. D. Christopher, Curr. HIV Res. 2017, 15, 411–421.
a) E. Cichero, S. Cesarini, P. Fossa, A. Spallarossa, L. Mosti, Eur. J. Med. Chem. 2009, 44, 2059–2070;.
b) L. A. Kohlstaedt, J. Wang, J. M. Friedman, P. A. Rice, T. A. Steitz, Science 1992, 256, 1783–1790.
a) N. Sluis‐Cremer, Viruses, 6, 2014, 2960–2973;.
b) P. L. Boyer, M. J. Currens, J. B. McMahon, M. R. Boyd, S. H. Hughes, J. Virol. 1993, 67, 2412–2420.
S. Bertagnolio, L. Hermans, M. R. Jordan, S. Avila‐Rios, C. Iwuji, A. Derache, E. Delaporte, A. Wensing, T. Aves, A. S. M. Borhan, A. Leenus, N. Parkin, M. Doherty, S. Inzaule, L. Mbuagbaw, J. Infect. Dis. 2021, 224, 377–388.
A. Kwara, G. Ramachandran, S. Swaminathan, Expert Opin. Drug Metab. Toxicol. 2010, 6, 55–68.
a) A. Singh, Artif. Intell. Chem. 2024, 2, 100071;.
b) A. Blanco‐González, A. Cabezón, A. Seco‐González, D. Conde‐Torres, P. Antelo‐Riveiro, Á. Piñeiro, R. Garcia‐Fandino, Pharmaceuticals 2023, 16, 891.
a) M. C. Steiner, K. M. Gibson, K. A. Crandall, Viruses, 12, 2020;.
b) L. Blassel, A. Tostevin, C. J. Villabona‐Arenas, M. Peeters, S. Hué, O. Gascuel, PLoS Comput. Biol. 2021, 17, e1008873.
N. Kumar, V. Acharya, Comput. Biol. Med. 2023, 153, 106525.
a) L. A. Machado, E. Krempser, A. C. R. Guimarães, Front. Drug Discov. 2022, 2, 954911;.
b) J. Zhou, J. Hao, L. Peng, H. Duan, Q. Luo, H. Yan, H. Wan, Y. Hu, L. Liang, Z. Xie, W. Liu, G. Zhao, J. Hu, Comput. Math. Methods Med. 2021, 2021, 5559338;.
c) A. K. Gao, T. B. Chen, V. L. Kouznetsova, I. F. Tsigelny, Artif. Intell. Chem. 2023, 1, 100014.
M. Néstor, C.‐R. Tania, M. Ophir, G.‐P. James, Inform. Med. Unlocked 2024, 48, 101512.
a) I. P. Singh, S. Bharate, K. Bhutani, Curr. Sci. 2005, 89, 269–290;.
b) S. S. Yang, G. M. Cragg, D. J. Newman, J. P. Bader, J. Nat. Prod. 2001, 64, 265–277.
B. F. Darst, K. C. Malecki, C. D. Engelman, BMC Genet. 2018, 19, 65.
H. Moriwaki, Y.‐S. Tian, N. Kawashita, T. Takagi, J. Cheminform. 2018, 10, 4.
Q. Zhang, P. Liu, X. Wang, Y. Zhang, Y. Han, B. Yu, Appl. Soft Comput. 2021, 99, 106921.
L. Fu, S. Shi, J. Yi, N. Wang, Y. He, Z. Wu, J. Peng, Y. Deng, W. Wang, C. Wu, A. Lyu, X. Zeng, W. Zhao, T. Hou, D. Cao, Nucleic Acids Res. 2024, 52, W422–W431.
a) A. Lavecchia, R. Costi, M. Artico, G. Miele, E. Novellino, A. Bergamini, E. Crespan, G. Maga, R. Di Santo, ChemMedChem 2006, 1, 1379–1390;.
b) R. K. Rawal, Y. S. Prabhakar, S. B. Katti, E. De Clercq, Bioorg. Med. Chem. 2005, 13, 6771–6776.
N. G. Sharaf, R. Ishima, A. M. Gronenborn, Biochemistry 2016, 55, 3864–3873.
I. Usach, V. Melis, J.‐E. Peris, J. Int. AIDS Soc. 2013, 16, 18567.
R. G. Huber, M. A. Margreiter, J. E. Fuchs, S. von Grafenstein, C. S. Tautermann, K. R. Liedl, T. Fox, J. Chem. Inf. Model. 2014, 54, 1371–1379.
A. Talukdar, B. Kundu, D. Sarkar, S. Goon, M. A. Mondal, Eur. J. Med. Chem. 2022, 236, 114304.
E. Sansinenea, F. Salazar, J. Jiménez, Á. Mendoza, A. Ortiz, Tetrahedron Lett. 2016, 57, 2604–2607.
H. Tse, Q. Gu, K.‐H. Sze, I. K. Chu, R. Y. T. Kao, K.‐C. Lee, C.‐W. Lam, D. Yang, S. S.‐C. Tai, Y. Ke, E. Chan, W.‐M. Chan, J. Dai, S.‐P. Leung, S.‐Y. Leung, K.‐Y. Yuen, J. Biol. Chem. 2017, 292, 19503–19520.
J. Ding, K. Das, C. Tantillo, W. Zhang, A. D. Clark, J.r., S. Jessen, X. Lu, Y. Hsiou, A. Jacobo‐Molina, K. Andries, R. Pauwels, H. Moereels, L. Koymans, P. A. J. Janssen, R. H. Smith J.r., M. K. Koepke, C. J. Michejda, S. H. Hughes, E. Arnold, Structure 1995, 3, 365–379.
R. Srivastava, S. K. Gupta, F. Naaz, P. S. Sen Gupta, M. Yadav, V. K. Singh, S. K. Panda, S. Biswal, M. K. Rana, S. K. Gupta, D. Schols, R. K. Singh, Comput. Biol. Chem. 2023, 106, 107910.
D. W. Wright, B. A. Hall, P. Kellam, P. V. Coveney, Biology 2012, 1, 222–244.
X. Gao, Z. Liu, W. Cui, L. Zhou, Y. Tian, Z. Zhou, PLoS One 2014, 9, e92357.
J. M. Seckler, K. J. Howard, M. D. Barkley, P. L. Wintrode, Biochemistry 2009, 48, 7646–7655.
D. Harris, R. Lee, H. S. Misra, P. K. Pandey, V. N. Pandey, Biochemistry 1998, 37, 5903–5908.
K. Das, J. D. Bauman, A. D. Clark, Y. V. Frenkel, P. J. Lewi, A. J. Shatkin, S. H. Hughes, E. Arnold, Proc. Natl. Acad. Sci. USA 2008, 105, 1466–1471.
S. K. Panda, P. S. Sen Gupta, S. Karmakar, S. Biswal, N. C. Mahanandia, M. K. Rana, J. Phys. Chem. Lett. 2023, 14, 10278–10284.
M. Rahimi, M. Taghdir, F. A. Joozdani, Sci. Rep. 2023, 13, 14179.
S. Tuske, J. Zheng, E. D. Olson, F. X. Ruiz, B. D. Pascal, A. Hoang, J. D. Bauman, K. Das, J. J. DeStefano, K. Musier‐Forsyth, P. R. Griffin, E. Arnold, Curr. Res. Struct. Biol. 2020, 2, 116–129.
G. G. Maisuradze, A. Liwo, H. A. Scheraga, J. Mol. Biol. 2009, 385, 312–329.
S. Genheden, U. Ryde, Expert Opin. Drug Discov. 2015, 10, 449‐461.
R. C. Bernardi, M. C. R. Melo, K. Schulten, Biochim. Biophys. Acta, Gen. Subj. 2015, 1850, 872‐877.
L. Shen, J. Shen, X. Luo, F. Cheng, Y. Xu, K. Chen, E. Arnold, J. Ding, H. Jiang, Biophys. J. 2003, 84, 3547–3563.
S.‐C. Nicolas, N. A. Temiz, B. Ivet, Curr. HIV Res. 2004, 2, 323–332.
B. Nizami, D. Sydow, G. Wolber, B. Honarparvar, Mol. BioSyst. 2016, 12, 3385–3395.
T. Cowen, K. Karim, S. Piletsky, Anal. Chim. Acta 2016, 936, 62–74.
a) I. Bahar, B. Erman, R. L. Jernigan, A. R. Atilgan, D. G. Covell, J. Mol. Biol. 1999, 285, 1023–1037;.
b) J. M. Seckler, M. D. Barkley, P. L. Wintrode, Biophys. J. 2011, 100, 144–153.
D. Yehorova, B. Di Geronimo, M. Robinson, P. M. Kasson, S. C. L. Kamerlin, Curr. Opin. Struct. Biol. 2024, 89, 102922.
S. Bowerman, J. Wereszczynski, in Methods in Enzymology, Vol. 578, (Ed: G. A. Voth), Academic Press, San Diego 2016, pp. 429–447.
H.‐T. Xu, M. Oliveira, E. L. Asahchop, M. McCallum, P. K. Quashie, Y. Han, Y. Quan, M. A. Wainberg, J. Virol. 2012, 86, 12983–12990.
a) J. Balzarini, J. Auwerx, F. Rodríguez‐Barrios, A. Chedad, V. Farkas, F. Ceccherini‐Silberstein, C. García‐Aparicio, S. Velázquez, E. De Clercq, C.‐F. Perno, M.‐J. Camarasa, F. Gago, Mol. Pharmacol. 2005, 68, 49;.
b) R. S. K. Vijayan, E. Arnold, K. Das, Proteins: Struct., Funct., Bioinf. 2014, 82, 815–829.
S.‐Y. Rhee, M. J. Gonzales, R. Kantor, B. J. Betts, J. Ravela, R. W. Shafer, Nucleic Acids Res. 2003, 31, 298–303.
E. Krissinel, K. Henrick, J. Mol. Biol. 2007, 372, 774–797.
Contributed Indexing:
Keywords: Ensemble; HIV‐1; MD Simulation; Machine Learning; NNRTI
Substance Nomenclature:
EC 2.7.7.49 (HIV Reverse Transcriptase)
0 (Reverse Transcriptase Inhibitors)
EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)
0 (Anti-HIV Agents)
0 (Reverse Transcriptase Inhibitors)
EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)
0 (Anti-HIV Agents)
Entry Date(s):
Date Created: 20250929 Date Completed: 20260114 Latest Revision: 20260114
Update Code:
20260130
DOI:
10.1002/asia.70340
PMID:
41021833
Database:
MEDLINE
*Further Information*
*The growing demand for new therapeutics highlights the need for intelligent, cost-effective, and scalable drug discovery strategies. Here, we present an artificial intelligence (AI)-based ensemble framework to accelerate the identification of small-molecule inhibitors against therapeutic targets. As a case study, we applied this approach to HIV-1 reverse transcriptase (HIV-1 RT), an essential enzyme in viral replication. Our stacking ensemble model, trained on a curated ChEMBL dataset, achieved high predictive performance (90.3% accuracy, 89.4% ROC-AUC) and was used to screen the Natural Products Atlas (NPA) database. Promising hits were evaluated through physicochemical and ADMET filters, molecular docking, and 1 µs molecular dynamics (MD) simulations. Compound NP1, which exhibited stable binding to the NNRTI binding pocket, outperformed the FDA-approved drug doravirine in post-MD characterizations. Network analysis further suggested potential allosteric regulation via residues N136 and E138. This flexible AI-MD pipeline provides an efficient strategy for discovering and repurposing inhibitors, with broad applicability to other therapeutic targets.
(© 2025 Wiley‐VCH GmbH.)*