Prolonged antibiotic therapy for the bacterial infections has resulted in high levels of antibiotic resistance. Initially, bacteria are susceptible to the antibiotics, but can gradually develop resistance. Treating such drug-resistant bacteria remains difficult or even impossible. Hence, there is a need to develop effective drugs against bacterial pathogens. The drug discovery process is time-consuming, expensive and laborious. The traditionally available drug discovery process initiates with the identification of target as well as the most promising drug molecule, followed by the optimization of this, in-vitro, in-vivo and in pre-clinical studies to decide whether the compound has the potential to be developed as a drug molecule. Drug discovery, drug development and commercialization are complicated processes. To overcome some of these problems, there are many computational tools available for new drug discovery, which could be cost effective and less time-consuming. In-silico approaches can reduce the number of potential compounds from hundreds of thousands to the tens of thousands which could be studied for drug discovery and this results in savings of time, money and human resources. Our review is on the various computational methods employed in new drug discovery processes.

Staphylococcus aureus infection is a healthcare problem to mankind for a considerable period of time. Once when it enters the bloodstream of an individual, it may potentially result in life‐threatening conditions. The resistance of S. aureus to various drugs such as penicillin, methicillin, gentamicin, erythromycin, and tetracycline have been well documented. Presently vancomycin is the drug of choice for methicillin resistant S. aureus. Scientists believe that S. aureus would completely develop resistance to vancomycin as well. Therefore there is a commensurate need to develop a drug to replace vancomycin. In the current study, we have focussed on FtsA, an important and vital cell division protein, which is found only in S. aureus and in other prokaryotic cells. We have carried out virtual screening process for FtsA against ZINC database, the best hit molecules obtained from the preliminary docking studies were subjected to SYBYL X 2.0 docking. The molecules ZINC74432848, ZINC37769607, and ZINC96896268 displayed the highest C‐score value of 4.89, 4.49, and 4.22, respectively. The top ranked molecule ZINC74432848 was observed to form 4 hydrogen bonds with FtsA. The simulation study reveals the greater stability of the FtsA‐ZINC74432848 complex. If the in vitro and in vivo study turns out affirmative, then ZINC74432848 could be developed as a potent drug for FtsA.

PurposeEffective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response.Experimental designWe performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference.ResultsWe identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K.ConclusionsOur results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.

The structural motifs of chalcones, flavones, and triazoles with varied substitutions have been studied for the antimalarial activity. In this study, 25 novel derivatives of chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage are docked with Plasmodium falciparum dihydroorotate dehydrogenase to establish their inhibitory activity against Plasmodium falciparum. The best binding conformation of the ligands at the catalytic site of dihydroorotate dehydrogenase are selected to characterize the best bound ligand using the best consensus score and the number of hydrogen bond interactions. The ligand namely (2E)-3-(4-{[1-(3-chloro-4-fluorophenyl)-1H-1, 2, 3-triazol-4-yl]methoxy}-3-methoxyphenyl-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one, is one the among the five best docked ligands, which interacts with the protein through nine hydrogen bonds and with a consensus score of five. To refine and confirm the docking study results, the stability of complexes is verified using Molecular Dynamics Simulations, Molecular Mechanics /Poisson-Boltzmann Surface Area free binding energy analysis, and per residue contribution for the binding energy. The study implies that the best docked Plasmodium falciparum dihydroorotate dehydrogenase-ligand complex is having high negative binding energy, most stable, compact, and rigid with nine hydrogen bonds. The study provides insight for the optimization of chalcone and flavone hybrids with 1, 2, 3-triazole linkage as potent inhibitors.

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Malathi, et al.: E. coli DHPS Inhibition by Ethyl IsoallocholateMedicinal rice varieties have defensive and therapeutic properties against many human disorders. Drug resistance has become a major problem in recent years. Escherichia coli have developed resistance to most of the antibiotics including sulfonamides that target dihydropteroate synthase. In the present study, we attempted to identify a novel inhibitor for the dihydropteroate synthase from a medicinal rice variety Karungkavuni. The phytochemical composition of the rice Karungkavuni was analysed through gas chromatography-mass spectrometry. The isolated compounds with reported antimicrobial activity were subjected to molecular docking procedures to understand the binding behaviour of the ligands with the target. These analyses revealed that ethyl iso-allocholate and 9,12,15-octadecatrienoic acid-2,3-dihydroxypropyl ester were the best binding compounds. Molecular dynamics studies revealed dihydropteroate synthase-ethyl iso-allocholate complex was more stable than other ligands throughout the simulation. Our study demonstrated that ethyl iso-allocholate isolated from Karungkavuni could serve as a potent inhibitor of dihydropteroate synthase.

Background Despite the fact that cervical cancer is preventable and curable in the early stages, it still remains to be a major public health problem in India. This study was conducted to assess the knowledge and awareness regarding the Human Papilloma Virus (HPV) vaccination among health care professionals working in a tertiary care hospital in urban India. Methods To this aim, we conducted a cross-sectional study among 318 health care professionals working in tertiary hospitals across Chennai, Tamil Nadu, India. Our research group designed a structured questionnaire with 31 items to assess the knowledge and attitudes on cervical cancer, its prevention, and HPV vaccination. Results Among the 318 respondents, 90.6% were aware of cervical cancer, 83.3% were aware that PAP (Papanicolaou) smear test detects cervical cancer, and 86.2% of the respondents knew that HPV causes cervical cancer. 29.2% of the eligible respondents underwent the screening against cervical cancer, and 19.8% of the study participants were vaccinated for HPV. Only 34.9% know that the HPV vaccine could be given to boys. The most common reason for not being vaccinated against HPV was the lack of awareness. In our study, 77.2% of the respondents were willing to be vaccinated and recommend HPV vaccination to their family members. Conclusion From this study, it was evident that there is a lack of awareness about HPV vaccination and its importance in preventing cervical cancer among healthcare professionals. Our finding clearly establishes the need to devise intervention programs to promote vaccination against HPV and periodical screening for cervical cancer among healthcare professionals.