In Silico Three Dimensional Pharmacophore Models to Aid the Discovery and Design of New Antimalarial Agents (original) (raw)
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European Journal of Medicinal Chemistry, 2004
A widely applicable three-dimensional QSAR pharmacophore model for antimalarial activity was developed from a set of 17 substituted antimalarial indolo[2,1-b]quinazoline-6,12-diones (tryptanthrins) that exhibited remarkable in vitro activity (below 100 ng/mL) against sensitive and multidrug-resistant Plasmodium falciparum malaria. The pharmacophore, which contains two hydrogen bond acceptors (lipid) and two hydrophobic (aromatic) features, was found to map well onto many well-known antimalarial drug classes including quinolines, chalcones, rhodamine dyes, Pfmrk cyclin dependent kinase inhibitors, malarial FabH inhibitors, and plasmepsin inhibitors. The phamacophore allowed searches for new antimalarial candidates from multiconformer 3D databases and enabled custom designed synthesis of new potent analogues.
Review, 2024
Plasmodium parasites, which cause the fever sickness known as malaria, are passed from infected female Anopheles mosquitoes to people through mosquito bites. Several parasite species, including P. vivax, P. falciparum, P. malaria, P. ovale, and P. knowlesi, are liable for human malaria. P. falciparum and P. vivax are the two most hazardous strains. The most pervasive and lethal malaria parasite on the continent of Africa is P. falciparum. In most nations outside of Sub-Saharan Africa, P. vivax is the most prevalent malaria parasite. The earliest symptoms of malaria, including fever, headaches, and chills, appear 10 to 15 days after an infected mosquito bite. These symptoms might be mild and difficult to identify from other infections. If untreated, P. falciparum malaria can progress to severe illness and death in less than 24 hours. By 2020, malaria will impact over half of the world's population. People with low immunity moving to regions with high malaria transmission, such as migrant workers, mobile populations, and travelers, are at a significantly higher risk of contracting malaria and developing severe disease. These individuals also include infants, young children, pregnant women, HIV/AIDS patients, and others. In this review we have utilized Chem3D software to visualized the 3D structure of Quinoline ring with its electronic structure which have provided numerous information regarding the stability of the quinoline scaffold. Additionally, we studied different marketed drug using this software and found its IC50 value against the several strains of the malaria causing agent. And we provided whole statistics regarding the severity of strain and better activity of the drug against the strain which will be helpful for the scientists to find out the better treatment for the malaria. We place these findings in an chronological context and suggested new options for identifying pharmacological targets and transmission- blocking techniques
A systematic review: Application of in silico models for antimalarial drug discovery
African Journal of Pharmacy and Pharmacology
Malaria remains the global public health problem due to the reemergence of drug resistance. There is an urgent need for development of new antimalarial candidates which are effective against resistant malaria parasite. This systematic review evaluates the published research studies that applied in silico modeling during the discovery process of antimalarial drugs. Literature searches were conducted using PubMed, EBSCO, EMBASE, and Web of Science to identify the relevant articles using the search terms "Malaria" "In silico model", "Computer-based drug design", "Antimalarial drug", and "Drug discovery". Only the articles published in English between 2008 and May 2015 were included in the analysis. A total of 17 relevant articles met the search criteria. Most articles are studies specific to Plasmodium falciparum targets; 3 and 1 articles, respectively involve target for P. vivax and liver stage of Plasmodium. Both structure-based and ligand-based approaches were applied to obtain lead antimalarial candidates. Two articles also assessed absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Confirmation of activity of the candidate leads by in vitro and/or in vivo assays were reported in some studies. Homology modelling, molecular docking, 2D-or 3D-QSAR and pharmacophore modeling are commonly applied methods. One study used de novo synthesis for lead identification and one study applied phylogenetic analysis for target identification/validation.
SN Applied Sciences
Quantitative structure–activity relationship studies conducted on forty-five (45) derivatives of 2-anilino 4-amino substituted quinazolines as malaria inhibitors to determine the structures responsible for their antimalarial properties and design novel derivatives with improved activities. The molecular descriptors generated were selected to develop the theoretical model using the genetic approximation component of the material studio. The developed model found to be a function of ATSC8c, GATS8i, SpMin1_Bhi, JGI10, and TDB6u descriptors, shows excellent statistical parameters (R2 = 0.7913, R2adj = 0.7553, Q2cv = 0.7112, LOF = 0.2125, and R2pred = 0.7650). The mean effect (MF) analysis revealed the descriptor SpMin1_Bhi, as the most influential by its largest percentage contribution (54%) to the developed model. The descriptor decodes the information on the first ionization potentials and was found to have positive MF. Hence, activity increases with increases the descriptor value. St...
… and modeling
A pharmacophore model has been developed for determining the essential structural requirements for antimalarial activity from the eight series of substituted 1,2,4-trioxanes. The best pharmacophore model possessing two aliphatic hydrophobic, one aromatic hydrophobic, one hydrogen-bond (H-bond) acceptor, and one H-bond acceptor (lipid) feature for antimalarial activity showed an excellent correlation coefficient for the training (r 2 training ) 0.85) and a fair correlation coefficient for the test set (r 2 test ) 0.51) molecules. The model predicts well to other known substituted 1,2,4-trioxanes including those which either are drugs or are undergoing clinical trials. In order to further validate this model, five substituted 1,2,4-trioxanes were synthesized from the generated focused library and screened for antimalarial activity. The observed activity of these molecules was consistent with the pharmacophore model, suggesting that the model may be useful in the design of potent antimalarial agents. Figure 1. (1) Artemether, (2) arteether, and (3) artemisinin.
Bangladesh Journal of Pharmacology, 2014
The present study was aim to develop a three dimensional quantitative structure-activity relationships (3D QSAR) model based on the structure of 4nerolidylcatechol (IC50 = 0.67 µM), a novel plant derived Plasmodium inhibitor and its derivatives for identification of efficient antimalarial lead. A statistically validated Partial Least-Squares (PLS) based Molecular Field Analysis (MFA) model was built up using the training set of eight 4-nerolidylcatechol derivatives and their diverse conformers. A statistically reliable model with good predictive power (cross-validated correlation coefficient q 2 = 0.769) was obtained. Hence, the generated model was used to screen a library of 30,000 compounds of chembridge database (http://www.chembridge.com). Results of drug likeness prediction and ADMET study has suggested six compounds as potential antimalarial/plasmodial lead.
Antimalarial drug discovery: in silico structural biology and rational drug design
2009
Malaria remains one of the most burdensome human infectious diseases, with a high rate of resistance outbreaks and a constant need for the discovery of novel antimalarials and drug targets. For several reasons, Plasmodial proteins are difficult to characterise structurally using traditional physical approaches. However, these problems can be partially overcome using a number of in silico approaches. This review describes the peculiarities of malaria proteins and then details various in silico strategies to select and allow descriptions of the molecular structures of drug target candidates as well as subsequent rational approaches for drug design. Chiefly, homology modelling with specific focus on unique aspects of malaria proteins including low homology, large protein size and the presence of parasite-specific inserts is addressed and alternative strategies including multiple sequence and structure-based prediction methods, samplingbased approaches that aim to reveal likely global or shared features of a Plasmodial structure and the value of molecular dynamics understanding of unique features of Plasmodial proteins are discussed. Once a detailed description of the drug target is available, in silico approaches to the specific design of an inhibitory drug thereof becomes invaluable as an economic and rational alternative to chemical library screening.
Journal of vector borne diseases
Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate...
International Journal of Molecular Sciences
Cost-effective therapy of neglected and tropical diseases such as malaria requires everlasting drug discovery efforts due to the rapidly emerging drug resistance of the plasmodium parasite. We have carried out computational design of new inhibitors of the enoyl-acyl carrier protein reductase (ENR) of Plasmodium falciparum (PfENR) using computer-aided combinatorial and pharmacophore-based molecular design. The Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) complexation QSAR model was developed for triclosan-based inhibitors (TCL) and a significant correlation was established between the calculated relative Gibbs free energies of complex formation (∆∆Gcom) between PfENR and TCL and the observed inhibitory potencies of the enzyme (IC50exp) for a training set of 20 known TCL analogues. Validation of the predictive power of the MM-PBSA QSAR model was carried out with the generation of 3D QSAR pharmacophore (PH4). We obtained a reasonable correlation between the relative Gib...
Journal of Medicinal Chemistry and Drug Design
A novel series of quinoline imines were designed by molecular manipulation approach using the principle of rational drug design. Newly designed quinoline imines were screened virtually for antimalarial effectiveness and also for drug-likeness using various in silico tools of drug design. The molecular docking was performed against P. falciparum parasite targeting specific cysteine protease falcipain 2 enzyme. In addition, drug-likeness and ADMET prediction studies were carried out using in silico tools. Our study reports antimalarial potential of novel quinoline imines as druglike molecules which can be further developed as potent antimalarial agents (falcipain 2 inhibitors) possibly against resistant P. falciparum parasite.