The emergence of nalidixic acid-resistant strains of Salmonella typhimurium remains to be a major public health problem. In particular, the substitution of Asn in place of Asp at the 87 loci in the GyrA of S. typhimurium was experimentally stated for nalidixic acid resistance. However, the data on the possible mechanism of nalidixic acid resistance are limited. In this study, I-Mutant2.0 and DUET program were employed to explore the impact of mutation on the stability of GyrA protein. Subsequently, molecular simulation techniques were employed to provide detailed information on the nalidixic acid-resistant associates with the D87N mutation in the GyrA of S. typhimurium. The binding free energy data depicts that nalidixic acid forms stable complex only with native-type GyrA than mutant (D87N) type GyrA protein. Moreover, our results theoretically suggest that hydrogen bonding formed by the Arg91 is certainly responsible for the GyrA of S. typhimurium drug selectivity. It is hoped that these evidences are immensely important for the development of new antibiotic and to overcome the nalidixic acid resistance in the near future. © 2015, Springer Science+Business Media New York.

Shanthi V

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Ramanathan K

Preethi B

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

&nbsp;

&nbsp;

VIT University

Applied Biochemistry and Biotechnology

Targeting anaplastic lymphoma kinase (ALK) is one of the important treatment strategies for the treatment of non-small cell lung cancer (NSCLC). In the present perspective, multidimensional approaches were used for the identification of ALK inhibitors. Initially, an e-pharmacophore model was generated using the PHASE algorithm and was used as a 3D query to screen 468,200 molecules of ASINEX database. Prior to the screening process, the model was evaluated for its significance and the ability to differentiate actives from inactives, using enrichment analysis. Subsequently, the hierarchical docking protocol and binding free energy calculations were instigated using GLIDE algorithm and Prime module, respectively. Further, the pharmacokinetic/pharmacodynamics (PK/PD) properties and toxicities of the hit compounds were envisaged respectively using QikProp program, Osiris explorer, and Protox-II algorithm. These approaches retrieved two hits namely BAS 00137817 and BAS 00680055 with acceptable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and higher affinity towards ALK protein. Additionally, density functional theory calculations and molecular dynamics simulations were performed to validate the inhibitory activity of the lead compounds. It is noteworthy to mention that all the hits constitute of particular scaffolds which play a major role in the downregulation of some ALK-positive lung cancer pathways. We speculate that the outcomes of this research are of substantial prominence in the rational designing of novel and efficacious ALK inhibitors.

Density Functional Theory and Molecular Simulation Studies for Prioritizing Anaplastic Lymphoma Kinase Inhibitors

The rapid spread of the Zika virus and its association with the abnormal brain development constitute a global health emergency. With a continuing spread of the mosquito vector, the exposure is expected to accelerate in the coming years. Despite number of efforts, there is still no proper vaccine or medicine to combat this virus. Of note, the NS2B-NS3 protein is proven to be the potential target for the Zika virus therapeutics. Hence, e-pharmacophore-based drug design strategy was employed to identify potent inhibitors of NS2B-NS3 protein from ASINEX database consisting of 467,802 molecules. A 3D e-pharmacophore model was generated using PHASE module of Schrödinger Suite. The generated model consists of one hydrogen bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R), ADDRR. The model was further evaluated for its ability to screen actives using enrichment analysis. Subsequently, high-throughput virtual screening protocol was employed, and the resultant hit molecules were also examined for its binding free energies and ADME properties using Prime MM-GBSA and Qikprop module of Schrodinger packages, respectively. Finally, the screened hit molecule was subjected to molecular dynamics simulation to examine its stability. Overall, the results from our analysis suggest that compound BAS 19192837 could be a potent inhibitor for the NS2B-NS3 protein of the Zika virus. It is also noteworthy to mention that our results are in good agreement with literature evidences. We hope that this result is of immense importance in designing potential drug molecules to combat the spread of Zika virus in the near future. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Exploring the Lead Compounds for Zika Virus NS2B-NS3 Protein: an e-Pharmacophore-Based Approach

The increasing death rates related to anaplastic lymphoma kinase (ALK)-positive lung cancer culminated in a significant interest in the discovery of novel inhibitors for ALK. In the present research work, pharmacophore-based 3D QSAR modeling and virtual screening strategy have been carried out to address these issues. Initially, a five-point pharmacophore model was developed using the biological data of 50 compounds which includes an FDA-approved ALK inhibitor, crizotinib. Using the generated pharmacophore, a 3D QSAR model was developed and used as a query to screen the DrugBank database. The model was found to be significant (R2 = 0.9696) with an excellent predictive accuracy (Q2 = 0.7652) as confirmed through validation of the both training and test molecule activities. Further, Glide docking score and absorption, distribution, metabolism and excretion properties were used to filter the screened candidates. Overall, our analysis results in three hits namely TR1, FAL, ZYW with higher docking scores, and good pharmaceutically relevant properties with increased CNS involvement. It is worth mentioning that FAL and ZYW were found to possess scaffolds with specific activity against ALK protein. We presume that the results obtained from this computational study are of immense importance in the rational designing of novel and more potent ALK inhibitors. © 2017, Springer Science+Business Media, LLC.

Drug Design for ALK-Positive NSCLC: an Integrated Pharmacophore-Based 3D QSAR and Virtual Screening Strategy

Neuraminidase (NA), a surface protein, facilitates the release of nascent virus and thus spreads infection. It has been renowned as a potential drug target for influenza A virus infection. The drugs such as oseltamivir, zanamivir, peramivir, and laninamivir are approved for the treatment of influenza infection. Additionally, investigational drugs namely MK2206, tamiphosphor, crenatoside, and dehydroepiandrosterone (DHEA) are also available for the treatment. However, recent outbreaks of highly pathogenic and drug-resistant influenza A strains highlighted the need to discover novel NA inhibitor. Keeping this in mind, in the current investigation, an effort was made to ascertain potent inhibitors using pharmacophore-based virtual screening and docking approach. A 3D pharmacophore model was generated based on the chemical features of approved and investigational NA inhibitors using PHASE module of Schrödinger suite. The model consists of two hydrogen bond acceptors (A), one hydrogen bond donor (D), and one positively charged group (P), AADP. Subsequently, molecules with same pharmacophoric features were screened from among the two million compounds available in the ZINC database using the generated pharmacophore hypothesis. Ligand filtration was also done to obtain an efficient collection of hit molecules by employing Lipinski “rule of five” using Qikprop module. Finally, the screened molecule was subjected to docking and molecular dynamic simulations to examine the inhibiting activity of the compounds. The results of our analysis suggest that “acebutolol hydrochloride” (156792) could be the promising candidates for the treatment of influenza A virus infection. © 2017, Springer Science+Business Media, LLC.

Discovery of Potent Neuraminidase Inhibitors Using a Combination of Pharmacophore-Based Virtual Screening and Molecular Simulation Approach

Crizotinib is an anticancer drug approved by FDA for the treatment of non-small cell lung cancer (NSCLC). The main target for crizotinib was anaplastic lymphoma kinase (ALK). However, evidences available indicate that C1156Y mutation in ALK confers resistance to crizotinib. Unfortunately, how mutation actually confers drug resistance is not well understood. Hence, in the present study computational approaches have been employed alongside KINOMEscan profiling technique to reveal the mechanism behind crizotinib resistance in ALK at a molecular level. The results of our analysis indicate that C1156Y mutation alters the conformation of the ALK binding pocket residues which results in a marked decrease in hydrogen bond interactions between crizotinib and ALK. This indicates that hydrogen bonding was a crucial effector of decreased binding affinity. Interestingly, the docking study also indicates that C1156Y mutation increases the affinity for ATP. Finally, our analysis theoretically suggests that M-1199 is a key residue responsible for the ALK drug selectivity. We certainly believe that these results may be immense importance for the molecular level understanding of crizotinib resistance pattern and also for designing a potential drug molecule for the treatment of lung cancer in the near future. © 2015 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

Molecular Informatics

Computational Investigation and Experimental Validation of Crizotinib Resistance Conferred by C1156Y Mutant Anaplastic Lymphoma Kinase

Crizotinib is the most effective and the only drug that has been approved for the treatment of anaplastic lymphoma kinase (ALK)-positive lung cancer. Reports suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene and F1174L is one such mutation. In this study, we used molecular docking and molecular dynamics (MD) approach to decipher the effect of F1174L mutation in drug-target binding. Docking results suggest that crizotinib was found to adopt the most promising conformations to the native-type ALK by identifying the M1199 residue as a prospective partner for making a hydrogen bond as compared to the mutant-type ALK. MD results showed that the average atom, especially atoms of the native-type ALK-crizotinib complex, movements were less, displayed less fluctuation, fast convergence of energy, and changes in geometry. This shows the stable binding of crizotinib with the native-type ALK in comparison to the mutant-type ALK. We believe that this study could be useful for the logical design of stronger, more selective, and more consistent ALK inhibitor against drug-resistant F1174L mutation.

Journal of Molecular Modeling

Exploring the structural and functional impact of the ALK F1174L mutation using bioinformatics approach

Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (&lt;1 %) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems. © 2012 Springer Science+Business Media, LLC.

Journal	Data powered by TypesetApplied Biochemistry and Biotechnology
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	0273-2289
Open Access	0