Mol-CycleGAN - a generative model for molecular optimization

Designing a molecule with desired properties is one of the biggest challenges in drug development, as it requires optimization of chemical compound structures with respect to many complex properties. To augment the compound design process we introduce Mol-CycleGAN - a CycleGAN-based model that generates optimized compounds with high structural similarity to the original ones. Namely, given a molecule our model generates a structurally similar one with an optimized value of the considered property. We evaluate the performance of the model on selected optimization objectives related to structural properties (presence of halogen groups, number of aromatic rings) and to a physicochemical property (penalized logP). In the task of optimization of penalized logP of drug-like molecules our model significantly outperforms previous results

Polyphenolic acetates: A newer anti-Mycobacterial therapeutic option

The objective of our research project was screening of various highly specific substrates of Acetoxy Drug: Protein Transacytylase (M.TAase) for antimycobacterial activity. Mycobacterial culture was done in Middlebrook’s 7H9 media. Protein purification (Mycobacterial Tranacetylase, M.TAase) was done by ion exchange chromatography and its demonstration was done on SDS- polyacrylamide gel electrophoresis (SDS-PAGE) and western blot. Middlebrook’s 7H9 broth was procured from Becton Dickinson. CM-Sepharose, DEAE-Sepharose and Q-Sephharose were purchased from Amersham Pharmacia. Anti acetyl lysine polyclonal antibody was purchased from Cell Signaling. The Middlebrook 7H9 medium was used for M. smegmatis culture. The media was prepared according to the manufacturer’s instructions. The various Polyphenol acetate compounds were tested for their antimycobacterial activities. Minimal inhibitory concentrations (MIC) were calculated by Alamar blue dye assay method. The GST protein was used as a receptor protein and purified Mycobacterial Glutamine Synthetase (GS) as TAase for acetylation by DAMC. To demonstrate the TAase catalyzed acetylation of GST by DAMC, purified M.TAase (GS) was preincubated with GST and DAMC followed by western blot using anti acetyl lysine antibody, which avidly react with the acetylated proteins. The growth pattern of M. smegmatis was diminished under the influence of various polyphenolic acetates (PA) tested for their anti-mycobacterial activity. DAMC and DAMC-5-carboxylic acid was found to have MIC of 40μg/ml whereas DAMC-6-carboxylic acid was reported to have MIC value of 35μg/ml and for ellagic acid tetra acetate (EATA) it was 60μg/ml. Previous work in our lab has led to discovery of a novel enzyme acetoxy drug: protein transacetylase (TAase), catalyzing transfer of acetyl group from various polyphenolic peracetate (PA) to certain receptor proteins such as cytochromes P-450, NADPH cytochrome reductase, nitric oxide synthase (NOS) has been established in various eukaryotic as well as prokaryotic sources. PA(s) irreversible inhibitors of mammalian CYP linked MFO, possibly due to modification of cytochrome p- 450 by acetylation in a reaction catalysed by M.TAase (GS) utilizing PA(s) as a donor of acetyl groups. Accordingly, it was hypothesized that the CYP51 of mycobacteria involved in the cell wall sterol synthesis could possibly be modified by our PA(s) through the novel unknown action of GS as transacetylase leading to the death of mycobacterial cell by way of acetylation catalyzed by acetoxy drug: protein transacetylase (M.TAase or GS).Keywords: Transacetylase; Glutamine synthetase; Mycobacterium smegmatis; Polyphenolic acetates; Acetoxy drug: protein transacetylas

Investigations of machining characteristics in upgraded MQL assisted turning of pure titanium alloy using evolutionary algorithms

Environmental protection is the major concern of any form of manufacturing industry today. As focus has shifted towards sustainable cooling strategies, minimum quantity lubrication (MQL) has proven its usefulness. The current survey intends to make the MQL strategy more effective while improving its performance. A Ranque–Hilsch vortex tube (RHVT) was implemented into the MQL process in order to enhance the performance of the manufacturing process. The RHVT is a device that allows for separating the hot and cold air within the compressed air flows that come tangentially into the vortex chamber through the inlet nozzles. Turning tests with a unique combination of cooling technique were performed on titanium (Grade 2), where the effectiveness of the RHVT was evaluated. The surface quality measurements, forces values, and tool wear were carefully investigated. A combination of analysis of variance (ANOVA) and evolutionary techniques (particle swarm optimization (PSO), bacteria foraging optimization (BFO), and teaching learning-based optimization (TLBO)) was brought into use in order to analyze the influence of the process parameters. In the end, an appropriate correlation between PSO, BFO, and TLBO was investigated. It was shown that RHVT improved the results by nearly 15% for all of the responses, while the TLBO technique was found to be the best optimization technique, with an average time of 1.09 s and a success rate of 90%

Mol-CycleGAN : a generative model for molecular optimization

During the drug design process, one must develop a molecule, which structure satisfies a number of physicochemical properties. To improve this process, we introduce Mol-CycleGAN – a CycleGAN-based model that generates compounds optimized for a selected property, while aiming to retain the already optimized ones. In the task of constrained optimization of penalized logP of drug-like molecules our model significantly outperforms previous results

Influence of surface engineering on 3D printed Ti lattice structure towards enhanced tissue integration: An in vitro and in vivo study

Reconstruction of segmental defects are popularly approached with surface engineered additively manufactured scaffolds owing to its enhanced post-surgery tissue integration properties. The present work is aimed at fabrication of Ti lattice structures using 3D printing, with a novel approach of silane chemistry-based surface modification of those Ti-surfaces with osteogenic peptides (OGP). The lattice structures with 0.6 mm strut-diameter having 0.5 mm inter-strut distance were chosen for fabrication using an extrusion-based 3D printing. Based on the evidence, it could be concluded that extrusion-based 3D printing is an optimal alternative as compared to those high cost incurring additive manufacturing processes. Therefore, OGP were grafted on the pristine Ti-surfaces using a silane chemistry based novel vapour deposition process. In vitro assessments of the surface modified scaffolds using human amniotic derived mesenchymal stem cells showed evidence of enhanced cell adhesion and viability. In vivo subcutaneous study in rat models of the surface modified Ti-scaffolds also showed enhanced tissue integration in terms of Collagen I deposition around the boundary of the tissue-integrated struts as compared to those of pristine scaffolds. The study has established that the novel surface modification technique is capable to engineer the Ti-surfaces towards enhanced tissue integration in vivo