Rahul Banerjee

Currently, vitalism stands as a discredited theory in the Western empirical sciences. However, the Indian analytical traditions, specifically the Jaina, Bauddha, Sankhya-Yoga, and the Vedanta, unanimously propose a vital energy “prana” or “jivitindriya” to bridge the explanatory gap between internal conscious states and physical states in the body. The philosophical development of vitalism both in the East and West follows independent and different trajectories. In this article, the view of consciousness as a transient internal state (found in the Abhidhamma ) and the modes of its interaction with physical states is critically examined. An attempt is made to find some parallels between the classical Abhidhamma model of consciousness and modern biophysical studies. How the model arose from meditative observation and the status of vital energy prana in mediating the interaction between internal and physical states, is discussed. The article ends by noting the application of these concepts in a therapy found in the Ayurvedic system of medicine.

According to the “jigsaw puzzle” model of protein folding, the isomorphism between sequence and structure is substantially determined by the specific geometry of side‐chain interactions, within the protein interior. In this work, we have attempted to predict the hydrophobic core of cyclophilin (LdCyp) from Leishmania donovani, utilizing a surface complementarity function, which selects for high goodness of fit between hydrophobic side‐chain surfaces, rather in the manner of assembling a three‐dimensional jigsaw puzzle. The computational core prediction method implemented here has been tried on two distinct scenarios, on the LdCyp polypeptide chain with native non‐core residues and all core residues initially set to alanine, on a poly‐glycine polypeptide chain. Molecular dynamics simulations appeared to indicate partial destabilization of the two designed sequences. However, experimental characterization of the designed sequences by circular dichroism (CD) spectroscopy and denaturant (GdmCl) induced unfolding, demonstrated disordered proteins. Stepwise reconstruction of the designed cores by cumulative sequential mutations identified the specific mutation (M122L) as primarily responsible for fold collapse and all design objectives were achieved upon rectifying this mutation. In summary, the study demonstrates regions of the core to contain highly specific (jigsaw puzzle‐like) interactions sensitive to any perturbations and a predictive algorithm to identify such regions. A mutation within the core has been identified which exercises an inordinate influence on the global fold, reminiscent of metamorphic proteins. In addition, the computational procedure could predict substantial regions of the core (given main‐chain coordinates) without any reference to non‐core residues.

Background: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL, in vitro and in animal model experiments. Methodology/Principal: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L . donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). Findings: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. Conclusions/Significance: All experiments affirmed the efficacy of suramin against L . donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.

The rapid emergence of drug resistant Leishmanial strains makes it imperative to continue the development of cheap and effective drugs against the parasite. Due to the absence of effective vaccines against leishmaniasis, current therapeutic measures exclusively rely on chemotherapy. Here we attempt, to identify novel antileishmanial from a list of known drugs determined from a previous bioinformatics study. Synergism between various drug combinations (involving netilmicin, suramin, paromomycin and curcumin) have been estimated to identify potent multidrug therapies to combat the disease. The drugs were screened against Leishmania promastigotes by utilizing the MTT assay and against intracellular amastigotes using murine Macrophage like tumor cell, RAW 264.7 as a host. In vitro drug interactions were tested for several drug combinations with a modified fixed ratio isobologram method against both Leishmania major and Leishmania donovani. This work reports the in vitro antileishmanial activity for the aminoglycoside netilmicin (for some Leishmania parasites) and the anti-trypanosomatid suramin. Synergism was also observed between paromomycin–suramin and netilmicin–curcumin.

Currently, considerable interest exists with regard to the dissociation of close packed aminoacids within proteins, in the course of unfolding, which could result in either wet or dry moltenglobules. The progressive disjuncture of residues constituting the hydrophobic core ofcyclophilin from L. donovani (LdCyp) has been studied during the thermal unfolding of the molecule, by molecular dynamics simulations. LdCyp has been represented as a surface contactnetwork (SCN) based on the surface complementarity (S_m) of interacting residues within themolecular interior. The application of S_m to side chain packing within proteins make it a very sensitive indicator of subtle perturbations in packing, in the thermal unfolding of the protein. Network based metrics have been defined to track the sequential changes in the disintegration ofthe SCN spanning the hydrophobic core of LdCyp and these metrics prove to be highly sensitive compared to traditional metrics in indicating the increased conformational (and dynamical) flexibility in the network. These metrics have been applied to suggest criteria distinguishing DMG, WMG and transition state ensembles and to identify key residues involved in crucial conformational/topological events during the unfolding process.

Leishmaniasis,a broad spectrum of diseases caused by several sister species of protozoa belonging to family trypanosomatidae and genus leishmania , generally affects poorer sections of the populace in third world countries. With the emergence of strains resistant to traditional therapies and the high cost of second line drugs which generally have severe side effects, it becomes imperative to continue the search for alternative drugs to combat the disease. In this work, the leishmanial genomes and the human genome have been compared to identify proteins unique to the parasite and whose structures (or those of close homologues) are available in the Protein Data Bank. Subsequent to the prioritization of these proteins (based on their essentiality, virulence factor etc.), inhibitors have been identified for a subset of these prospective drug targets by means of an exhaustive literature survey. A set of three dimensional protein-ligand complexes have been assembled from the list of leishmanial drug targets by culling structures from the Protein Data Bank or by means of template based homology modeling followed by ligand docking with the GOLD software. Based on these complexes several structure based pharmacophores have been designed and used to search for alternative inhibitors in the ZINC database. This process led to a list of prospective compounds which could serve as potential antileishmanials. These small molecules were also used to search the Drug Bank to identify prospective lead compounds already in use as approved drugs. Interestingly, paromomycin which is currently being used as an antileishmanial drug spontaneously appeared in the list, probably giving added confidence to the ‘scaffold hopping’ computational procedures adopted in this work. The report thus provides the basis to experimentally verify several lead compounds for their predicted antileishmanial activity and includes several useful data bases of prospective drug targets in leishmania, their inhibitors and protein – inhibitor three dimensional complexes.