3D-QSAR analysis of cycloguanil derivatives as inhibitors of A16V+S108T mutant Plasmodium falciparum dihydrofolate reductase enzyme

Adane, Legesse; Bharatam, Prasad V.

doi:10.1016/j.jmgm.2009.09.001

Cited by 15 publications

(3 citation statements)

References 58 publications

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“…Yellow crystals, yield: 86%; M.p: 143-145 uC; MW: 387.74; R f : 0.55; FT-IR (n max ; cm 21 KBr): 3289.56 (N-H secondary), 3055.70 (C-H broad), 1548.28-1446.06 (aromatic CLN); 1 H-NMR (400 MHz, CDCl 3 -d 6 , TMS) d (ppm) 4H,4xCH,4H,4xCH, Ar-H), 3.62 (br, s, 2H,2x NH); 13 C-NMR (100MHz, CDCl 3 ) d (ppm): 173.56,168.85,148.26,143.16,131.36,126.23;Mass: 388.10 H,2.21;N,15.37. Found: C,39.53;H,2.20;N,15.34.…”

Section: -Chloro-4-isothiocyanatoquinoline (3)mentioning

confidence: 99%

“…[10][11][12][13][14] 1,3,5triazine, which is another core scaffold in clinically used antimalarial drugs, for instance in cycloguanil, chlorcycloguanil, clociguanil, and WR99210, has gained attraction due to its potential to deliver potent molecules. [14][15][16] Recently, conjugates of 4-aminoquinoline with 1,3,5-triazine have been employed widely as novel DHFR inhibitors. 16,18 Our research endeavour to discover newer hybrid molecules of 1,3,5-triazine as antibacterial, 19 antimalarial, 17 antifungal 20 agents continues.…”

Section: Introductionmentioning

confidence: 99%

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Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Bhat¹,

Singh²,

Gahtori³

et al. 2013

RSC Adv.

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Section: -Chloro-4-isothiocyanatoquinoline (3)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Bhat¹,

Singh²,

Gahtori³

et al. 2013

RSC Adv.

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“…Two compounds from this class of series were found to be active with the IC 50 values of 100 μM and 400 nM against wild-type PfDHFR (Adane et al, 2014). Quantitative structure-activity relationship (QSAR) studies have also been extensively carried out on these known antifolates and their derivatives to identify structural features responsible for the differences in anti-plasmodial activities with respect to their electrostatic, steric, and hydrophobic nature (Adane & Bharatam, 2009;Basak & Mills, 2010;Basak, Mills, & Hawkins, 2011;Hecht, Cheung, & Fogel, 2008;Maitarad, Kamchonwongpaisan, et al, 2009;Maitarad, Saparpakorn, et al, 2009;Ojha & Roy, 2011;Santos-Filho, Mishra, & Hopfinger, 2001;Sivaprakasam, Tosso, & Doerksen, 2009). The studies reported slightly different binding alignment of the ligands to the mutant form of an enzyme as compared to the wild-type form.…”

Section: Introductionmentioning

confidence: 99%

Origins of the specificity of inhibitor P218 toward wild-type and mutantPfDHFR: a molecular dynamics analysis

Abbat

Jain

Bharatam

2014

Journal of Biomolecular Structure and Dynamics

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Molecular dynamics simulations were performed to evaluate the origin of the antimalarial effect of the lead compound P218. The simulations of the ligand in the cavities of wild-type, mutant Plasmodium falciparum Dihydrofolate Reductase (PfDHFR) and the human DHFR revealed the differences in the atomic-level interactions and also provided explanation for the specificity of this ligand toward PfDHFR. The binding free energy estimation using Molecular Mechanics Poisson-Boltzmann Surface Area method revealed that P218 has higher binding affinity (~ -30 to -35 kcal/mol) toward PfDHFR (both in wild-type and mutant forms) than human DHFR (~ -22 kcal/mol), corroborating the experimental observations. Intermolecular hydrogen bonding analysis of the trajectories showed that P218 formed two stable hydrogen bonds with human DHFR (Ile7 and Glu30), wild-type and double-mutant PfDHFR's (Asp54 and Arg122), while it formed three stable hydrogen bonds with quadruple-mutant PfDHFR (Asp54, Arg59, and Arg122). Additionally, P218 binding in PfDHFR is stabilized by hydrogen bonds with residues Ile14 and Ile164. It was found that mutant residues do not reduce the binding affinity of P218 to PfDHFR, in contrast, Cys59Arg mutation strongly favors inhibitor binding to quadruple-mutant PfDHFR. The atomistic-level details explored in this work will be highly useful for the design of non-resistant novel PfDHFR inhibitors as antimalarial agents.

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Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme

Adane

Bharatam

2010

J Mol Model

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Design and discovery of new potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), equally active against both the wild-type and mutant strains, is urgently needed. In this study, a computer-aided molecular design approach that involved ab initio molecular orbital and density functional theory calculations, along with molecular electrostatic potential analysis, and molecular docking studies was employed to design 15 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme. Visual inspection of the binding modes of the compounds demonstrated that they all interact, via H-bond interactions, with key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14) similar to those of WR99210 (3) in the active site of the enzymes used in the study. These interactions are known to be essential for enzyme inhibition. These compounds showed better or comparable binding affinities to that of the bound ligand (WR99210). In silico toxicity predictions, carried out using TOPKAT software, also indicated that the compounds are non-toxic.

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3D-QSAR analysis of cycloguanil derivatives as inhibitors of A16V+S108T mutant Plasmodium falciparum dihydrofolate reductase enzyme

Cited by 15 publications

References 58 publications

Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Antimalarial activity and docking studies of novel bi-functional hybrids derived from 4-aminoquinoline and 1,3,5-triazine against wild and mutant malaria parasites as pf-DHFR inhibitor

Origins of the specificity of inhibitor P218 toward wild-type and mutantPfDHFR: a molecular dynamics analysis

Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme

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