Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Deciding confluence of certain term rewriting systems in polynomial time

We present a characterization of confluence for term rewriting systems, which is then refined for special classes of rewriting systems. The refined characterization is used to obtain a polynomial time algorithm for deciding the confluence of ground term rewrite systems. The same approach also shows the decidability of confluence for shallow and linear term rewriting systems. The decision procedure has a polynomial time complexity under the assumption that the maximum arity of a function symbol in the signature is a constant.     

Magnetic and martensitic transitions in Ni-Fe-Ga alloy

The ferromagnetic shape memory alloy with nominal composition Ni₅₄Fe₁₉Ga₂₇ is investigated by Ac susceptibility and resistivity measurements. The alloy shows long-range ferromagnetic order below 290 K. The anomaly due to the martensitic transition is observed in the susceptibility and resistivity data in the temperature range around 220 K, which is associated with clear thermal hysteresis. Minor hysteresis loop technique was used to investigate the phase coexistence across the martensitic transition, and our analysis indicate that both martensite and austenite phases mutually coexist in the region of hysteresis.     

Thermal decomposition of a generation 4.5 PAMAM dendrimer platinum drug conjugate

A nanoscale multivalent platinum drug based on a poly(amidoamine) [PAMAM] dendrimer (generation 4.5, carboxylate surface) has been synthesized and fully characterized using a variety of spectroscopic, chromatographic and thermal methods. Treatment of the dendrimer with an aqueous solution containing an excess diaquo(cis-1,2-diaminocyclohexane)platinum(II) produces a conjugate containing approximately forty (diaminocyclohexane)platinum(II) moieties at the surface of the dendrimer. This material undergoes smooth two-stage thermal decomposition to provide residual platinum oxide reflecting the platinum loading in the drug.     

Dynamic stability of uncertain laminated beams subjected to subtangential loads

Because of the inherent complexity of fiber-reinforced laminated composites, it can be challenging to manufacture composite structures according to their exact design specifications, resulting in unwanted material and geometric uncertainties. Thus the understanding of the effect of uncertainties in laminated structures on their static and dynamic responses is highly important for a reliable design of such structures. In this research, we focus on the probabilistic stability analysis of laminated structures subject to subtangential loading, a combination of conservative and nonconservative tangential loads, using the dynamic criterion. In order to study the dynamic behavior by including uncertainties into the problem, three models were developed: exact Monte Carlo simulation, sensitivity-based Monte Carlo simulation, and probabilistic FEA. These methods were integrated into the existing finite element analysis. Also, perturbation and sensitivity analysis have been used to study nonconservative problems to study the stability analysis using the dynamic criterion.