Comparative Molecular Field Analysis and Molecular Docking Studies on Quinolinone Derivatives Indicate Potential Hepatitis C Virus Inhibitors.

Presently, there are no effective vaccines and anti-virals for the prevention and treatment of Hepatitis C virus infections and hence there is an urgent need to develop potent HCV inhibitors. In this study, we have carried out molecular docking, molecular dynamics and 3D-QSAR on heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone series using NS5B protein. Total of 41 quinolinone derivatives is used for molecular modeling study. The binding conformation and hydrogen bond interaction of the docked complexes were analyzed to model the inhibitors. We identified the molecule XXXV that had a higher affinity with NS5B. The molecular dynamics study confirmed the stability of the compound XXXV-NS5B complex. The developed CoMFA descriptors parameters, which were calculated using a test set of 13 compounds, were statistically significant. Our results will provide useful insights and lead to design potent anti-Hepatitis C virus molecules.

Identification of potential inhibitors for Klebsiella pneumoniae carbapenemase-3: a molecular docking and dynamics study.

Klebsiella pneumoniae (K. pneumoniae) is a Gram-negative bacterium, which is a leading causal agent for nosocomial infections. Penicillin, cephalosporin and carbapenems along with the inhibitors such as tazobactam, sulbactam and clavulanic acid are prescribed for the treatment of K. pneumoniae infections. Prolonged exposure to ß-lactam antibiotics leads to the development of resistance. The major reason for the ß-lactam resistance in K. pneumoniae is the secretion of the enzyme K. pneumoniae carbapenemase (KPC). Secretion of KPC-2 and its variant KPC-3 by the K. pneumoniae strains causes resistance to both the substrate imipenem and the ß-lactamase inhibitors. Hence, molecular docking and dynamics studies were carried out to analyze the resistance mechanism of KPC-2-imipenem and KPC-3-imipenem at the structural level. It reveals that KPC-3-imipenem has the highest c-score value of 4.03 with greater stability than the KPC-2-imipenem c-score value of 2.36. Greater the interaction between the substrate and the ß-lactamase enzyme, higher the chances of hydrolysis of the substrate. Presently available ß-lactamase inhibitors are also ineffective against KPC-3-expressing strains. This situation necessitates the need for development of novel and effective inhibitors for KPC-3. We have carried out the virtual screening process to identify more effective inhibitors for KPC-3, and this has resulted in ZINC48682523, ZINC50209041 and ZINC50420049 as the best binding energy compounds, having greater binding affinity and stability than KPC-3-tazobactam interactions. Our study provides a clear understanding of the mechanism of drug resistance and provides valuable inputs for the development of inhibitors against KPC-3 expressing K. pneumoniae. Communicated by Ramaswamy H. Sarma.

Mechanism of imipenem resistance in metallo-ß-lactamases expressing pathogenic bacterial spp. and identification of potential inhibitors: An in silico approach.

The World Health Organization reports that millions of people around the world are infected with antibiotic-resistant bacteria. Such resistance is more common in Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae strains because of the expression of the metallo-ß-lactamases (MBLs) namely Imipenemase (IMP)-1, IMP-2, New Delhi metallo-ß-lactamases-, Verona imipenemase (VIM)-4, VIM-5, and VIM-7. We did an in silico analysis to understand the resistance mechanism of imipenem at the structural level. Our modeling studies reveal that the VIM-4-imipenem complex has highest binding energy and forms a stable complex as indicated by a consensus score (C-score) value of 5.44. The intense interaction between the substrate and the ß-lactamases leads to the increased hydrolysis of the substrate resulting in rapid hydrolysis of the antibiotic imipenem by VIM-4. Virtual screening of compounds from the ZINC database targeting VIM-4 was done, and we found compound ZINC44608383 as the high binding energy compound with the C-score value of 5.58. This compound could be exploited for inhibitor design and development. The current study helps us to understand the resistance mechanism of imipenem in MBL-expressing strains. Also, we have identified a probable inhibitor for VIM-4. We believe that our results will be useful for researchers in designing potent inhibitors for VIM-4.

Insights on inhibition of Plasmodium falciparum plasmepsin I by novel epoxyazadiradione derivatives - molecular docking and comparative molecular field analysis.

In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) - comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q2) value of 0.967 and the non-cross-validated correlation coefficient (r2) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r2(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied. Communicated by Ramaswamy H. Sarma.

FtsA as a cidal target for Staphylococcus aureus: Molecular docking and dynamics studies.

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.

Bioinformatics approaches for new drug discovery: a review.

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.

In-Silico molecular docking and simulation studies on novel chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage as vital inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

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.

MurB as a target in an alternative approach to tackle the Vibrio cholerae resistance using molecular docking and simulation study.

Cholera is a serious threat to a large population in the under developed countries. Though oral rehydration therapy is the preferred choice of treatment, the use of antibiotics could reduce the microbial load in the case of severity. The use of antibiotics is also sought in the scenarios where there is problem with access to clean water. However, Vibrio cholera (V. cholerae) strains have developed resistance to antibiotics such as amoxicillin, ampicillin, chloramphenicol, doxycycline, erythromycin, and tetracycline. In this work, we have addressed the resistance issue by targeting MurB protein which is essential for the cell wall biosynthesis in V. cholerae. 20 Phytochemical compounds were chosen to screen the potential inhibitors against V. cholerae to avoid the complications faced by synthesis of small molecules. The molecular docking and dynamics study indicates that quercetin is the most potential and stable inhibitor of Murb.

Exploring the resistance mechanism of imipenem in carbapenem hydrolysing class D beta-lactamases OXA-143 and its variant OXA-231 (D224A) expressing Acinetobacter baumannii: An in-silico approach.

Acinetobacter baumannii (A. baumannii), is a Gram negative, coccobacilli and is associated with nosocomial infections. The bacterium has developed resistance to all known classes of antibiotics. Multi-drug resistant A. baumannii infections have been treated with the carbapenem group of antibiotics like imipenem and meropenem. Recent reports indicate that A. baumannii has acquired resistance to imipenem due to the secretion of carbapenem hydrolysing class D beta-lactamases (CHDLs). Such CHDLs found in carbapenem resistant A. baumannii belongs to OXA-143 and its variant OXA-231, which has Alanine (A) in place of Aspartic acid (D) at sequence position 224. The mutation of the OXA-231 CHDL alters the catalytic activity of the enzyme. Hence, the present study was carried out to find the probable mechanism of imipenem resistance in OXA-143 and OXA-231 (D224A) CHDLs expressing A. baumannii by employing molecular docking and dynamics. Methods Our study reveals that OXA-143 CHDL-imipenem complex has more binding affinity than OXA-231 (D224A) CHDL-imipenem complex. Our results indicate that there is a strong binding affinity of OXA-143 with imipenem when compared with OXA-243 and this mechanism might be the probable reason for imipenem resistance in OXA-143 expressing A. baumannii strains.

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts.

PURPOSE: Effective 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 DESIGN: We 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. RESULTS: We 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. CONCLUSIONS: Our 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.

Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum ß-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium that frequently causes nosocomial infections. New generation cephalosporins and ß-lactams along with inhibitors are used for the treatment of opportunistic bacterial infections. The indiscriminate use of antibiotics has led to the emergence of bacterial resistance. Carbapenem class of antibiotics like imipenem and meropenem are currently the final line of antibiotics for the treatment of infections caused by multidrug-resistant P. aeruginosa. Recent reports indicate that P. aeruginosa has acquired resistance to imipenem through a class D oxacillinase-OXA-10 extended spectrum ß-lactamase (ESBL). OXA-10 ESBL is encoded by the gene blaOXA-10. There is an urgent need to develop OXA-10 ESBL non-hydrolysing inhibitors. We have attempted to locate OXA-10 ESBL inhibitors by performing molecular docking and molecular dynamics studies on OXA-10 ESBL with imipenem analogues from ZINC database as well as employing imipenem to understand the mechanism of resistance at the structural level. Our in-silico analysis of imipenem analogues reveals that ZINC44672480 has ideal characteristics for a potent OXA-10 ESBL non-hydrolysing inhibitor. We believe that the results from our study will provide valuable insights into the mechanism of drug resistance and aid in designing potent inhibitors against OXA-10 ESBL producing P. aeruginosa.