Structural characterization of plasmodial aminopeptidase: a combined molecular docking and QSAR-based in silico approaches


Aminopeptidase M1 (PfAM1) is one of the key enzymes involved in the development of new antimalarials. To accelerate the discovery of inhibitors with selective activity against PfAM1 and microsomal neutral aminopeptidase (pAPN), in the present work, the optimum comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were built based on PfAM1 and pAPN inhibitors. The results of the developed 3D-QSAR models were as follows: PfAM1/CoMFA: \( R_{\text{cv}}^{2} \) = 0.740, \( R_{\text{pred}}^{2} \) = 0.7781; PfAM1/CoMSIA: \( R_{\text{cv}}^{2} \) = 0.740, \( R_{\text{pred}}^{2} \) = 0.7354; pAPN/CoMFA: \( R_{\text{cv}}^{2} \) = 0.612, \( R_{\text{pred}}^{2} \) = 0.7318; pAPN/CoMSIA: \( R_{\text{cv}}^{2} \) = 0.609, \( R_{\text{pred}}^{2} \) = 0.7480, and the models derived from MLR, PLSR and SVR methods provided high R2 values of 0.6960, 0.6965, 0.7971 for PfAM1, 0.7700, 0.7697, 0.8228 for pAPN and Q2 of 0.7004, 0.7004, 0.5632 for PfAM1, 0.7551, 0.7566 and 0.8394 for pAPN, respectively, indicating that the developed 3D-QSAR and 2D-QSAR models possess good ability for prediction of the relative compound activities. Furthermore, all inhibitors were docked into the active site of the PfAM1 and pAPN receptors, the hydrogen-bond interactions between the compound 33 with Glu497, Glu463 and Arg489 of the PfAM1, and the compound 4 with Ala348, Glu384 and Phe467 of the receptor pAPN are able to help to stabilize the conformation. The above results would provide helpful clues to predicting the binding activity of novel inhibitors and the foundation for understanding the interaction mechanism between the inhibitors and the receptors.

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  1. 1.

    World Health Organization (2015) World malaria report 2015. World Health Organization, Geneva

    Google Scholar 

  2. 2.

    Mueller I, Zimmerman PA, Reeder JC (2007) Plasmodium malariae and Plasmodium ovale—the ‘bashful’ malaria parasites. Trends Parasitol 23(6):278–283.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Collins WE (2012) Plasmodium knowlesi: a malaria parasite of monkeys and humans. Annu Rev Entomol 57(1):107–121.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Nosten F, Rogerson SJ, Beeson JG, McGready R, Mutabingwa TK, Brabin B (2004) Malaria in pregnancy and the endemicity spectrum: what can we learn? Trends Parasitol 20(9):425–432.

    Article  PubMed  Google Scholar 

  5. 5.

    Dev V, Phookan S, Sharma VP, Dash AP, Anand SP (2006) Malaria parasite burden and treatment seeking behavior in ethnic communities of Assam, Northeastern India. J Infect 52(2):131–139.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Nadjm B, Behrens RH (2012) Malaria: an update for physicians. Infect Dis Clin North Am 26(2):243–259.

    Article  PubMed  Google Scholar 

  7. 7.

    Collins WE (2012) Plasmodium knowlesi: a malaria parasite of monkeys and humans. Annu Rev Entomol 57:107–121.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Paola C, Paolo B, Chiara F, Carlo M, Giampietro P (2011) Fatal myocarditis in course of Plasmodium falciparum infection: case report and review of cardiac complications in malaria. Case Rep Med 2011(4):202083.

    Article  Google Scholar 

  9. 9.

    Reyburn H (2010) New WHO guidelines for the treatment of malaria: quality assured diagnosis of malaria in Africa is a major challenge. BMJ Br Med J 341(7765):161–162.

    Article  Google Scholar 

  10. 10.

    Neurath H, Walsh KA (1976) Role of proteolytic enzymes in biological regulation (a review). Proc Natl Acad Sci USA 73(11):3825–3832.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Rabbani G, Kaur J, Ahmad E, Khan RH, Jain SK (2014) Structural characteristics of thermostable immunogenic outer membrane protein from Salmonella enterica serovar Typhi. Appl Microbiol Biotechnol 98(6):2533–2543.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    López-Otín C (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283(45):30433–30437.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Neurath H (1984) Evolution of proteolytic enzymes. Science 224(4647):350–357.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Johnson DE (2000) Noncaspase proteases in apoptosis. Leukemia 14(9):1695–1703.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Joseph K, Ghebrehiwet B, Kaplan AP (2001) Activation of the kinin-forming cascade on the surface of endothelial cells. Biol Chem 382(1):71–75.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407(6801):258.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Barros C, Crosby JA, Moreno RD (1996) Early steps of sperm–egg interactions during mammalian fertilization. Cell Biol Int 20(1):33–39.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Davidson DJ, Higgins DL, Castellino FJ (1990) Plasminogen activator activities of equimolar complexes of streptokinase with variant recombinant plasminogens. Biochemistry 29(14):3585–3590.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Sim RB, Laich A (2000) Serine proteases of the complement system. Biochem Soc Trans 28(5):545–550.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Collen D, Lijnen HR (1986) The fibrinolytic system in man. Crit Rev Oncol Hematol 4(3):249–301.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    LeMosy EK, Hong CC, Hashimoto C (1999) Signal transduction by a protease cascade. Trends Cell Biol 9(3):102–107.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Van den Steen PE, Opdenakker G, Wormald MR, Dwek RA, Rudd PM (2001) Matrix remodelling enzymes, the protease cascade and glycosylation. Biochim Biophys Acta 1528(2–3):61–73.

    Article  PubMed  Google Scholar 

  23. 23.

    Selvarajan S, Lund LR, Takeuchi T, Craik CS, Werb Z (2001) A plasma kallikrein-dependent plasminogen cascade required for adipocyte differentiation. Nat Cell Biol 3(3):267–275.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cheng XW, Huang Z, Kuzuya M, Okumura K, Murohara T (2011) Cysteine protease cathepsins in atherosclerosis-based vascular disease and its complications. Hypertension 58(6):978–986.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Turk V, Turk B, Turk D (2001) Lysosomal cysteine proteases: facts and opportunities. EMBO J 20(17):4629–4633.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Siklos M, BenAissa M, Thatcher GR (2015) Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors. Acta Pharm Sin B 5(6):506–519.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398(6727):518–522.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398(6727):522–525.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Ye Y, Lukinova N, Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila presenilin mutants. Nature 398(6727):525–529.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B (2001) Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. J Immunol 167(11):6441–6446.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    McLauchlan J, Lemberg MK, Hope G, Martoglio B (2002) Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21(15):3980–3988.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Mucha A, Drag M, Dalton JP, Kafarski P (2010) Metallo-aminopeptidase inhibitors. Biochimie 92(11):1509–1529.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Kinch LN, Ginalski K, Grishin NV (2006) Site-2 protease regulated intramembrane proteolysis: sequence homologs suggest an ancient signaling cascade. Protein Sci 15(1):84–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    McGowan S, Porter CJ, Lowther J, Stack CM, Golding SJ, Skinner-Adams TS, Trenholme KR, Teuscher F, Donnelly SM, Grembecka J, Mucha A, Kafarski P, Degori R, Buckle AM, Gardiner DL, Whisstock JC, Dalton JP (2009) Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase. Proc Natl Acad Sci USA 106(8):2537–2542.

    Article  PubMed  Google Scholar 

  35. 35.

    McGowan S, Oellig CA, Birru WA, Caradoc-Davies TT, Stack CM, Lowther J, Skinner-Adams T, Mucha A, Kafarski P, Grembecka J, Trenholme KR, Buckle AM, Gardiner DL, Dalton JP, Whisstock JC (2010) Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases. Proc Natl Acad Sci USA 107(6):2449–2454.

    Article  PubMed  Google Scholar 

  36. 36.

    Overall CM, Kleifeld O (2006) Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6(3):227–239.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Haq SK, Rabbani G, Ahmad E, Atif SM, Khan RH (2010) Protease inhibitors: a panacea? J Biochem Mol Toxicol 24(4):270–277.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Rabbani G, Baig MH, Ahmad K, Choi I (2017) Protein–protein interactions and their role in various diseases and their prediction techniques. Curr Protein Pept Sci.

    Article  Google Scholar 

  39. 39.

    Wu Y, Wang X, Liu X, Wang Y (2003) Data-mining approaches reveal hidden families of proteases in the genome of malaria parasite. Genome Res 13(4):601.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Klemba M, Gluzman I, Goldberg DE (2004) A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J Biol Chem 279(41):43000–43007.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Withers-Martinez C, Jean L, Blackman MJ (2004) Subtilisin-like proteases of the malaria parasite. Mol Microbiol 53(1):55–63.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Poreba M, McGowan S, Skinner-Adams TS, Trenholme KR, Gardiner DL, Whisstock JC, To J, Salvesen GS, Dalton JP, Drag M (2012) Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum. PLoS One 7(2):e31938.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Skinner-Adams TS, Lowther J, Teuscher F, Stack CM, Grembecka J, Mucha A, Kafarski P, Trenholme KR, Dalton JP, Gardiner DL (2007) Identification of phosphinate dipeptide analog inhibitors directed against the Plasmodium falciparum M17 leucine aminopeptidase as lead antimalarial compounds. J Med Chem 50(24):6024–6031.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Stack CM, Lowther J, Cunningham E, Donnelly S, Gardiner DL, Trenholme KR, Skinner-Adams TS, Teuscher F, Grembecka J, Mucha A, Kafarski P, Lua L, Bell A, Dalton JP (2007) Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development. J Biol Chem 282(3):2069–2080.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Skinner-Adams TS, Peatey CL, Anderson K, Trenholme KR, Krige D, Brown CL, Stack C, Nsangou DM, Mathews RT, Thivierge K, Dalton JP, Gardiner DL (2012) The aminopeptidase inhibitor CHR-2863 is an orally bioavailable inhibitor of murine malaria. Antimicrob Agents Chemother 56(6):3244–3249.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Chen L, Lin YL, Peng G, Li F (2012) Structural basis for multifunctional roles of mammalian aminopeptidase N. Proc Natl Acad Sci USA 109(44):17966–17971.

    Article  PubMed  Google Scholar 

  47. 47.

    Finn RD, Mistry J, Tate J, Coggill P, Heger A, Pollington JE, Gavin OL, Gunasekaran P, Ceric G, Forslund K (2008) The Pfam protein families database. Nucleic Acids Res 32(1):D138.

    CAS  Article  Google Scholar 

  48. 48.

    Thunnissen MM, Nordlund P, Haeggström JZ (2001) Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation. Nat Struct Mol Biol 8(2):131–135.

    CAS  Article  Google Scholar 

  49. 49.

    Wong AH, Zhou D, Rini JM (2012) The X-ray crystal structure of human aminopeptidase N reveals a novel dimer and the basis for peptide processing. J Biol Chem 287(44):36804–36813.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Yang Y, Liu C, Lin YL, Li F (2013) Structural insights into central hypertension regulation by human aminopeptidase A. J Biol Chem 288(35):25638–25645.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Hermans SJ, Ascher DB, Hancock NC, Holien JK, Michell BJ, Chai SY, Morton CJ, Parker MW (2015) Crystal structure of human insulin-regulated aminopeptidase with specificity for cyclic peptides. Protein Sci 24(2):190–199.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Velmourougane G, Harbut MB, Dalal S, McGowan S, Oellig CA, Meinhardt N, Whisstock JC, Klemba M, Greenbaum DC (2011) Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase. J Med Chem 54(6):1655–1666.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Kannan Sivaraman K, Paiardini A, Sienczyk M, Ruggeri C, Oellig CA, Dalton JP, Scammells PJ, Drag M, McGowan S (2013) Synthesis and structure–activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum. J Med Chem 56(12):5213–5217.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Paiardini A, Bamert RS, Kannan-Sivaraman K, Drinkwater N, Mistry SN, Scammells PJ, McGowan S (2015) Screening the medicines for malaria venture “malaria box” against the Plasmodium falciparum aminopeptidases, M1, M17 and M18. PLoS ONE 10(2):e0115859.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Ruggeri C, Drinkwater N, Sivaraman KK, Bamert RS, McGowan S, Paiardini A (2015) Identification and validation of a potent dual inhibitor of the P. falciparum M1 and M17 aminopeptidases using virtual screening. PLoS ONE 10(9):e0138957.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Sahi S, Rai S, Chaudhary M, Nain V (2014) Modeling of human M1 aminopeptidases for in silico screening of potential Plasmodium falciparum alanine aminopeptidase (PfA-M1) specific inhibitors. Bioinformation 10(8):518–525.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Sahi S, Raj U, Chaudhary M, Nain V (2014) Modelling of human leucyl aminopeptidases for in silico off target binding analysis of potential Plasmodium falciparum leucine aminopeptidase (PfA-M17) specific inhibitors. Recent Pat Endocr Metab Immune Drug Discov 8(3):191–201.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Chaudhary M, Singh V, Anvikar AR, Sahi S (2016) Screening and in vitro evaluation of potential Plasmodium falciparum leucyl aminopeptidase inhibitors. Curr Comput Aided Drug Des 12(4):282–293.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Mistry SN, Drinkwater N, Ruggeri C, Sivaraman KK, Loganathan S, Fletcher S, Drag M, Paiardini A, Avery VM, Scammells PJ, McGowan S (2014) Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. J Med Chem 57(21):9168–9183.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Drinkwater N, Vinh NB, Mistry SN, Bamert RS, Ruggeri C, Holleran JP, Loganathan S, Paiardini A, Charman SA, Powell AK, Avery VM, McGowan S, Scammells PJ (2016) Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions. Eur J Med Chem 110:43–64.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Skinner-Adams TS, Stack CM, Trenholme KR, Brown CL, Grembecka J, Lowther J, Mucha A, Drag M, Kafarski P, McGowan S, Whisstock JC, Gardiner DL, Dalton JP (2010) Plasmodium falciparum neutral aminopeptidases: new targets for anti-malarials. Trends Biochem Sci 35(1):53–61.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Flipo M, Beghyn T, Leroux V, Florent I, Deprez BP, Deprezpoulain RF (2007) Novel selective inhibitors of the zinc plasmodial aminopeptidase PfA-M1 as potential antimalarial agents. J Med Chem 50(6):1322–1334.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Deprezpoulain R, Flipo M, Piveteau C, Leroux F, Dassonneville S, Florent I, Maes L, Cos P, Deprez B (2012) Structure–activity relationships and blood distribution of antiplasmodial aminopeptidase-1 inhibitors. J Med Chem 55(24):10909–10917.

    CAS  Article  Google Scholar 

  64. 64.

    Guha R, Serra JR, Jurs PC (2004) Generation of QSAR sets with a self-organizing map. J Mol Graph Model 23(1):1–14.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36(22):3219–3228.

    CAS  Article  Google Scholar 

  66. 66.

    Chao Y, Wong ILK, Wen BJ, Tao J, Chow LMC, Sheng BW (2014) Modification of marine natural product ningalin B and SAR study lead to potent p-glycoprotein inhibitors. Mar Drugs 12(10):5209.

    CAS  Article  Google Scholar 

  67. 67.

    Clark M, Cramer RD, Van Opdenbosch N (1989) Validation of the general purpose tripos 5.2 force field. J Comput Chem 10(8):982–1012.

    CAS  Article  Google Scholar 

  68. 68.

    Thaimattam R, Daga PR, Banerjee R, Iqbal J (2005) 3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases. Bioorg Med Chem 13(15):4704–4712.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Uddin R, Naz A, Akhtar N, Haq ZU (2013) Development of robust QSAR model using rapid overlay of crystal structures (ROCS) based alignment: a test case of Tubulin inhibitors. Med Chem Res 22(7):3229–3241.

    CAS  Article  Google Scholar 

  70. 70.

    Pirhadi S, Ghasemi JB (2010) 3D-QSAR analysis of human immunodeficiency virus entry-1 inhibitors by CoMFA and CoMSIA. Eur J Med Chem 45(11):4897–4903.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Iii RDC, Bunce JD, Patterson DE, Frank IE (1988) Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies. Mol Inform 7(1):18–25.

    Article  Google Scholar 

  72. 72.

    Wang F, Ma Z, Li Y, Wang J, Wang Y (2012) Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis. J Mol Model 18(7):3227–3242.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Todeschini R, Consonni V, Mauri A, Pavan M (2005) DRAGON, 5.3. Talete srl, Milan

    Google Scholar 

  74. 74.

    Wang Y, Li Y, Ding J, Jiang Z, Chang Y (2008) Estimation of bioconcentration factors using molecular electro-topological state and flexibility. SAR QSAR Environ Res 19(3–4):375.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Hansch C, Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley, New York.

    Google Scholar 

  76. 76.

    Sjöström M, Wold S, Lindberg W, Persson J-Å, Martens H (1983) A multivariate calibration problem in analytical chemistry solved by partial least-squares models in latent variables. Anal Chim Acta 150:61–70.

    Article  Google Scholar 

  77. 77.

    Ding G, Chen J, Qiao X, Huang L, Lin J, Chen X (2006) Quantitative relationships between molecular structures, environmental temperatures and solid vapor pressures of PCDD/Fs. Chemosphere 62(7):1057–1063.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Wold S, Sjöström M, Eriksson L (2001) PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 58(2):109–130.

    CAS  Article  Google Scholar 

  79. 79.

    Smola AJ, Schölkopf B (2004) A tutorial on support vector regression. Stat Comput 14(3):199–222.

    Article  Google Scholar 

  80. 80.

    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14):1639–1662.;2-B

    CAS  Article  Google Scholar 

  81. 81.

    Kumar DT, Doss CGP (2016) Chapter nine—investigating the inhibitory effect of Wortmannin in the hotspot mutation at codon 1047 of PIK3CA kinase domain: a molecular docking and molecular dynamics approach. Adv Protein Chem Struct Biol 102:267.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Zhou Z, Madura JD (2004) CoMFA 3D-QSAR analysis of HIV-1 RT nonnucleoside inhibitors, TIBO derivatives based on docking conformation and alignment. J Chem Inf Comput Sci 44(6):2167.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Liu M, He L, Hu X, Liu P, Luo HB (2010) 3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor. Bioorg Med Chem Lett 20(23):7004–7010.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Caballero J, Garriga M, Fernández M (2006) 2D Autocorrelation modeling of the negative inotropic activity of calcium entry blockers using Bayesian-regularized genetic neural networks. Bioorg Med Chem 14(10):3330–3340.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Schuur JH, Paul Selzer A, Gasteiger J (1996) The coding of the three-dimensional structure of molecules by molecular transforms and its application to structure–spectra correlations and studies of biological activity. J Chem Inf Model 36(2):334–344.

    CAS  Article  Google Scholar 

  86. 86.

    Hemmer MC, Steinhauer V, Gasteiger J (1999) Deriving the 3D structure of organic molecules from their infrared spectra. Vib Spectrosc 19(1):151–164.

    CAS  Article  Google Scholar 

  87. 87.

    Wang Y, Shao Y, Wang Y, Fan L, Yu X, Zhi X, Yang C, Qu H, Yao X, Xu H (2012) Synthesis and quantitative structure–activity relationship (QSAR) study of novel isoxazoline and oxime derivatives of podophyllotoxin as insecticidal agents. J Agric Food Chem 60(34):8435–8443.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Mao Y, Li Y, Hao M, Zhang S, Ai C (2012) Docking, molecular dynamics and quantitative structure–activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors. J Mol Model 18(5):2185–2198.

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Consonni V, Todeschini R (2009) Molecular descriptors for chemoinformatics, volume I: alphabetical listing. Wiley, New York

    Google Scholar 

  90. 90.

    Chamjangali A (2009) Modelling of cytotoxicity data (CC50) of anti-HIV 1-[5-chlorophenyl) sulfonyl]-1H-pyrrole derivatives using calculated molecular descriptors and Levenberg–Marquardt artificial neural network. Chem Biol Drug Des 73(4):456.

    CAS  Article  Google Scholar 

  91. 91.

    Todeschini R, Gramatica P (1998) New 3D molecular descriptors: the WHIM theory and QSAR applications. Perspect Drug Discov Des 9–11(4):355–380.

    Article  Google Scholar 

  92. 92.

    Li J, Sun J, He Z (2007) Quantitative structure–retention relationship studies with immobilized artificial membrane chromatography II: partial least squares regression. J Chromatogr A 1140(1–2):174.

    CAS  Article  PubMed  Google Scholar 

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Wang, F., Hu, X. & Zhou, B. Structural characterization of plasmodial aminopeptidase: a combined molecular docking and QSAR-based in silico approaches. Mol Divers 23, 965–984 (2019).

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  • Aminopeptidase
  • CoMFA
  • CoMSIA
  • 2D-QSAR
  • Molecular docking