Further, stability and predictive ability of this model was validated with test set. The lactate dehydrogenase of P. The water molecules were deleted and hydrogen atoms were added. No use, distribution or reproduction is permitted which does not comply with these terms. The antimalarial drug, chloroquine, interacts with lactate dehydrogenase from Plasmodium falciparum. A grid space of 1. A set of 37 compounds Figure 1 , which covers most potent, moderate potent as well as least active, was selected from our previous work Ahmed et al.
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Detailed analysis of grid-based molecular docking: Though chloroquine and other quinolone act primarily by inhibiting heme polymerization Egan and Ncokazi,chloroquine interacts, in addition, specifically with Pf LDH in the NADH binding pocket, occupying a position similar to that of the adenyl ring cofactor. In computer aided structure-based drug design, molecular docking is one of tools employed to study the putative geometry of a protein-ligand complex. Two probe types are used to compute the energy grids that indicate electrostatic and steric effects.
We have developed the predictive GridBasedTemp model using docking based alignment for Pf LDH inhibitory activity of tricyclic guanidine compounds. The Leave-one-out LOO method of cross-validation was used for validation of predictive ability of model with the training set. Antimalarial activity of potential inhibitors of plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.
Synthesis and biological evaluation of tricyclic guanidine analogues of Batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal, and anti-HIV activities. The predictive IC 50 nafeee are shown in Table 2.
Because of emergence of chloroquine resistant strain, it is an urgent demand to design and develop 3dd new anti-malarial drug. Total of 37 compounds were divided into training set 29 compounds and test set 8 compounds. You can login by using one of your existing accounts. The lactate dehydrogenase of P. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds naees on tricyclic guanidine derivatives and to predict activities of new inhibitors.
Moreover, there has been rapid increase in resistance to drugs by P.
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In enzyme binding site, Glu is nmae near to this region which acts hydrogen bond acceptor forming hydrogen bond with hydrogen atom present on nitrogen of tricyclic ring, thus strengthen the binding and increase activity. Figure 5B indicates the predictive values of pIC 50 of test set by this model are in agreement with the experimental values with r 2 value of 0.
Binding of compound 37 in active site of enzyme LDH. Antiprotozoal and antimicrobial activities of O-alkylated and formylated acylphloroglucinols. Figure 5A indicate the correlation between the experimental and predictive pIC 50 of compounds and results are listed in Table 2. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms.
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The antimalarial drug, chloroquine, interacts with lactate dehydrogenase from Plasmodium falciparum. In silico design of novel and highly selective lysine-specific histone demethylase inhibitors. Molecular field analysis contour map displayed with compound 37 and superimposition on active site of Pf LDH A electrostatic interaction contour map; blue color represents anfees coefficients while red color represents negative coefficients B steric interaction contour map; green color indicates positive coefficients and yellow color indicates negative coefficients.
Namf conformations with lowest energy were selected as the most probable binding conformation for each ligand.
To increase the activity larger negative value of predicted activitya molecule should have positive electrostatic potential in the blue area and negative in the red area. The docked chloroquine in binding pocket of enzyme is shown in Figure 2. Docked chloroquine in the binding pocket of LDH enzyme.
Docking studies showed that there is a very strong correlation between in silico and in vitro results. Login Register Login using. Malarial infection caused by Plasmodium falciparum is the most deadly among all pathogens and challenge for developing countries Bharate et al.
Protein chemistry and structure: Recently, we have synthesized tricyclic guanidine naame compounds Figure 1 and reported the anti-malarial activity by using plasmodial Nam activity as measure of inhibition against various strains of P.
Introduction Malarial infection caused by Plasmodium falciparum is the most deadly among all pathogens and challenge for developing countries Bharate et al.
For training set, Partial Least Square analysis showed cross validated q 2 of 0. This help in rational-based synthesis of new compounds Vieth and Cummins,