Tabish Qidwai

QSAR and Docking Based Semi-Synthesis and In Vivo Evaluation of Artemisinin Derivatives for Antimalarial Activity

To screen the active antimalarial novel artemisinin derivatives, a QSAR modeling approach was used. QSAR model showed high correlation (r(2)= 0.83 and rCV(2)= 0.81) and indicated that Connectivity Index (order 1, standard), Connectivity Index (order 2, standard), Dipole Moment (debye), Dipole Vector X (debye) and LUMO Energy (eV) well correlate with activity. High binding likeness on antimalarial target plasmepsin was detected through molecular docking. Active artemisinin derivatives showed significant activity and indicated compliance with standard parameters of oral bioavailability and ADMET. The active artemisinin derivatives namely, β-Artecyclopropylmether HMCP (A3), β- Artepipernoylether (PIP-1) (A4) and 9-(β-Dihydroartemisinoxy)methyl anthracene (A5) were semi-synthesized and characterized based on its (1)H and (13)C NMR spectroscopic data and later activity tested in vivo on mice infected with multidrug resistant strain of P. yoelii nigeriensis. Predicted results were successfully validated by in vivo experiments.

Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway.

QSAR, Docking and ADMET Studies of Artemisinin Derivatives for Antimalarial Activity Targeting Plasmepsin II, a Hemoglobin-Degrading Enzyme from P. falciparum

This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r(2)) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV(2)) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

Antimalarial Drug Targets and Drugs Targeting Dolichol Metabolic Pathway of Plasmodium falciparum

Because of mutation and natural selection, development of drug resistance to the existing antimalarial is the major problem in malaria treatment. This problem has created an urgent need of novel antimalarial drug targets as well as lead compounds. The important characteristic of malaria is that it shows the phenomenon of balanced polymorphisms. Several traits have been selected in response to disease pressure. Therefore such factors must be explored to understand the pathogenesis of malaria infection in human host. Apicoplast, hub of metabolism is present in Plasmodium falciparum (causative agent of falciparum malaria) having similarities with plant plastid. Among several pathways in apicoplast, Dolichol metabolic pathway is one of the most important pathway and has been known to play role in parasite survival in the human host. In P.falciparum, a phosphorylated derivative of Dolichol participates in biosynthesis of glycoproteins. Several proteins of this pathway play role in post translational modifications of proteins involved in the signal transduction pathways, regulation of DNA replication and cell cycle. This pathway can be used as antimalarial drug target. This report has explored progress towards the study of proteins and inhibitors of Dolichol metabolic pathway. For more comprehensive analysis, the host genetic factors and drug-protein interaction have been covered.

Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for Plasmodium falciparum

Emergence of rapid drug resistance to existing antimalarial drugs in Plasmodium falciparum has created the need for prediction of novel targets as well as leads derived from original molecules with improved activity against a validated drug target. The malaria parasite has a plant plastid-like apicoplast. To overcome the problem of falciparum malaria, the metabolic pathways in parasite apicoplast have been used as antimalarial drug targets. Among several pathways in apicoplast, isoprenoid biosynthesis is one of the important pathways for parasite as its multiplication in human erythrocytes requires isoprenoids. Therefore targeting this pathway and exploring leads with improved activity is a highly attractive approach. This report has explored progress towards the study of proteins and inhibitors of isoprenoid biosynthesis pathway. For more comprehensive analysis, antimalarial drug-protein interaction has been covered.

Hemoglobin degradation pathway of Plasmodium falciparum as antimalarial drug target

: Plasmepsins, falcipains and aminopeptidases are Plasmodium falciparum proteases involved in human host hemoglobin degradation and other processes like erythrocyte invasion and rupture. Antimalarial drug resistance and natural selection in parasite are important reasons that create the urgent need of novel targets and lead compounds to overcome the burden of malaria. This report explored progress of the study covering proteases and their inhibitors specific to hemoglobin degradation. Additionally, in silico predicted antimalarial targets, balancing selection and drug-protein interaction are included.

Exploring putative molecular mechanisms of human pyruvate kinase enzyme deficiency and its role in resistance against Plasmodium falciparum malaria.

Malaria is the third most prevalent cause of global mortality and is an interesting case of evolutionary selection. In response to high frequency of malaria infection, several host genetic factors have been selected, such as Hemoglobin variants, Glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency. Among these popular host genetic factors, deficiency of pyruvate kinase enzyme is one of the most important factor that provide resistance against malaria. Regulation of this enzyme at the level of transcription is important and several factors may play crucial role in regulation of this enzyme. DNA sequence variation and epigenetic factors modifying transcriptional regulation of gene have been explored in context of several diseases. In the present study, we explored the factors modifying transcription regulation of pyruvate kinase gene with the help of Bioinformatics tools. On the basis of our predictions we hypothesize that any factor that reduces the availability (level) or activity of pyruvate kinase enzyme must play a strong role in resistance to malaria. Thus, factors reducing the activity (loss of function) or level of pyruvate kinase have been selected to provide resistance against malaria primarily in endemic regions.

Biomedical Importance of Host Genetic Factors in Infectious Diseases

Tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome and malaria are the three most profound cause of death worldwide. In developing country tuberculosis is a serious problem. It is estimated that one third of the world’s population is infected with M. tuberculosis; however, only a minority (10%) of those infected ever develop clinical disease (Corbett et al., 2003). Such clinical diversity suggests that factors other than bacterial infection alone determine disease development. Tuberculosis (TB) is a significant disease affecting both humans and animals. Susceptibility to Mycobacterium tuberculosis is relatively higher in humans than other primates and guinea pigs. Cattle, rabbits and cats are susceptible to M. bovis and are quite resistant to M. tuberculosis.