Analysis of a novel class A β-lactamase OKP-B-6 of Klebsiella quasipneumoniae: structural characterisation and interaction with commercially available drugs

BACKGROUND Gram-negative and Gram-positive bacteria produce beta-lactamase as factors to overcome beta-lactam antibiotics, causing their hydrolysis and impaired antimicrobial action. Class A beta-lactamase contains the chromosomal sulfhydryl reagent variable (SHV, point mutation variants of SHV-1), LEN (Klebsiella pneumoniae strain LEN-1), and other K. pneumoniae beta-lactamase (OKP) found mostly in Klebsiella's phylogroups. The SHV known as extended-spectrum β-lactamase can inactivate most beta-lactam antibiotics. Class A also includes the worrisome plasmid-encoded Klebsiella pneumoniae carbapenemase (KPC-2), a carbapenemase that can inactivate most beta-lactam antibiotics, carbapenems, and some beta-lactamase inhibitors. OBJECTIVES So far, there is no 3D crystal structure for OKP-B, so our goal was to perform structural characterisation and molecular docking studies of this new enzyme. METHODS We applied a homology modelling method to build the OKP-B-6 structure, which was compared with SHV-1 and KPC-2 according to their electrostatic potentials at the active site. Using the DockThor-VS, we performed molecular docking of the SHV-1 inhibitors commercially available as sulbactam, tazobactam, and avibactam against the constructed model of OKP-B-6. FINDINGS From the point of view of enzyme inhibition, our results indicate that OKP-B-6 should be an extended-spectrum beta-lactamase (ESBL) susceptible to the same drugs as SHV-1. MAIN CONCLUSIONS This conclusion advantageously impacts the clinical control of the bacterial pathogens encoding OKP-B in their genome by using any effective, broad-spectrum, and multitarget inhibitor against SHV-containing bacteria.

Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

In Silico Screening Of Zinc Database For Discovery Of Novel Urease Inhibitors As A Remedy To Gastro-Duodenal Ulcer Caused By Helicobacter Pylori

Design and synthesis of novel urease inhibitors taking center stage now days with specific attention as a remedy to Helicobacter pylori infection. A number of inhibitors fail in vivo and in clinical trial owing to the toxicity and hydrolytic profile. In the present study, we are making an attempt to screen a large small molecule database, ZINC, for a potential urease inhibitor. The structure based drug discovery approach has been adopted with acceptable ADMET parameters so that the lead molecules may have fair chances of passing in vitro and in vivo trails. The lead molecule in our study, with ID ZINC90446454 is a urea derivative and predicted to be nontoxic. It comes out to be a promising drug candidate with pKd value 7.83, LE 0.429 and LD50 value 10100 mg/kg body weight. Its sulfanyl derivative, with predicted high LD50 (10100 mg/kg body weight), exhibits the feasibility of a disulfide covalent bond with Cys321 in the active site. The derivative may serve as a novel covalent inhibitor with high specificity, high potency and low toxicity. The derivative, in future, may be a successful drug candidate for H. pylori induced gastro-duodenal ulcer.

Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

BACKGROUND Owing to increased spending on pharmaceuticals since 2010, discussions about rising costs for the development of new medical technologies have been focused on the pharmaceutical industry. Computational techniques have been developed to reduce costs associated with new drug development. Among these techniques, virtual high-throughput screening (vHTS) can contribute to the drug discovery process by providing tools to search for new drugs with the ability to bind a specific molecular target. OBJECTIVES In this context, Brazilian malaria molecular targets (BraMMT) was generated to execute vHTS experiments on selected molecular targets of Plasmodium falciparum. METHODS In this study, 35 molecular targets of P. falciparum were built and evaluated against known antimalarial compounds. FINDINGS As a result, it could predict the correct molecular target of market drugs, such as artemisinin. In addition, our findings suggested a new pharmacological mechanism for quinine, which includes inhibition of falcipain-II and a potential new antimalarial candidate, clioquinol. MAIN CONCLUSIONS The BraMMT is available to perform vHTS experiments using OCTOPUS or Raccoon software to improve the search for new antimalarial compounds. It can be retrieved from www.drugdiscovery.com.br or download of Supplementary data.

From Medicinal Chemistry to Human Health: Current Approaches to Drug Discovery for Cancer and Neglected Tropical Diseases

ABSTRACT Scientific and technological breakthroughs have compelled the current players in drug discovery to increasingly incorporate knowledge-based approaches. This evolving paradigm, which has its roots attached to the recent advances in medicinal chemistry, molecular and structural biology, has unprecedentedly demanded the development of up-to-date computational approaches, such as bio- and chemo-informatics. These tools have been pivotal to catalyzing the ever-increasing amount of data generated by the molecular sciences, and to converting the data into insightful guidelines for use in the research pipeline. As a result, ligand- and structure-based drug design have emerged as key pathways to address the pharmaceutical industry's striking demands for innovation. These approaches depend on a keen integration of experimental and molecular modeling methods to surmount the main challenges faced by drug candidates - in vivo efficacy, pharmacodynamics, metabolism, pharmacokinetics and safety. To that end, the Laboratório de Química Medicinal e Computacional (LQMC) of the Universidade de São Paulo has developed forefront research on highly prevalent and life-threatening neglected tropical diseases and cancer. By taking part in global initiatives for pharmaceutical innovation, the laboratory has contributed to the advance of these critical therapeutic areas through the use of cutting-edge strategies in medicinal chemistry.

Computer Aided Drug Designing

Designing of drugs and their development are a time and resource consuming process. There is an increasing effort to introduce the role of computational approach to chemical and biological space in order to organise the design and development of drugs and their optimisation. The role of Computer Aided Drug Designing (CADD) are nowadays expressed in Nanotechnology, Molecular biology, Biochemistry etc. It is a diverse discipline where various forms of applied and basic researches are interlinked with each other. Computer aided or in Silico drug designing is required to detect hits and leads. Optimise/ alter the absorption, distribution, metabolism, excretion and toxicity profile and prevent safety issues. Some commonly used computational approaches include ligand-based drug design, structure-based drug design, and quantitative structure-activity and quantitative structure-property relationships. In today's world, due to an avid interest of regulatory agencies and, even pharmaceutical companies in advancing drug discovery and development process by computational means, it is expected that its power will grow as technology continues to evolve. The main purpose of this review article is to give a brief glimpse about the role Computer Aided Drug Design has played in modern medical science and the scope it carries in the near future, in the service of designing newer drugs along with lesser expenditure of time and money

Strategies for designing influenza neuraminidase inhibitors and research progress / 国际药学研究杂志

Nowadays, influenza is still a big threat to human health and could cause mass mortality during pandemic years. The viral surface protein, neuraminidase (NA), plays an important role in the life cycle of influenza virus and has been proved as the major antiinfluenza target. Since the X-ray crystal structure of NA was defined in 1983, the application of structure-based drug design and computational chemistry have greatly contributed to the development of NA inhibitors (NAIs). Till now, two antiinfluenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) are available. In this article, we will illustrate the strategies of NAIs' design according to the development of the two drugs and also present some recent progress in this field.