Computer-Assisted and Data Driven Approaches for Surveillance, Drug Discovery, and Vaccine Design for the Zika Virus.

Human life has been at the edge of catastrophe for millennia due diseases which emerge and reemerge at random. The recent outbreak of the Zika virus (ZIKV) is one such menace that shook the global public health community abruptly. Modern technologies, including computational tools as well as experimental approaches, need to be harnessed fast and effectively in a coordinated manner in order to properly address such challenges.

Computational Approaches for the Design of Mosquito Repellent Chemicals.

Background: In view of many current mosquito-borne diseases there is a need for the design of novel repellents.

Objective: The objective of this article is to review the results of the researches carried out by the authors in the computer-assisted design of novel mosquito repellents.

Methods: Two methods in the computational design of repellents have been discussed: a) Quantitative Structure Activity Relationship (QSAR) studies from a set of repellents structurally related to DEET using computed mathematical descriptors, and b) Pharmacophore based modeling for design and discovery of novel repellent compounds including virtual screening of compound databases and synthesis of novel analogues.

Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus.

In a previous study, twelve antimalarial compounds, amodiaquine (AQ) and derivatives, were shown to have potent anti-dengue viral (DENV) activity by using the stable DENV2 Renilla luciferase reporter replicon expressing BHK-21 cells, infectivity (plaque), and the qRT-PCR assays. In this study, we performed molecular modeling on these compounds to determine their stereo-electronic properties required for optimal antiviral activity. Based on the similarity of calculated stereo-electronic profiles, specifically the electrostatic potential profiles of the compounds, and in silico screening of related compounds from literature, we identified three additional compounds, Quinacrine (QC), Mefloquine (MQ), and GSK369796.

In vitro efficacy of 2,N-bisarylated 2-ethoxyacetamides against Plasmodium falciparum.

Investigation of a series of 2,N-bisarylated 2-ethoxyacetamides resulted in the identification of four inhibitors 5, 20, 24, 29 with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains. These compounds are analogs of structurally-related 1,3-bisaryl-2-propen-1-ones (chalcones), the latter showing efficacy in vitro but not in a malaria-infected mouse. The 2,N-bisarylated 2-ethoxyacetamides (e.

Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase.

Utilizing our previously reported in silico pharmacophore model for reactivation efficacy of oximes, we present here a discovery of twelve new non-oxime reactivators of diisopropylfluorophosphate (DFP)-inhibited acetylcholinesterase (AChE) obtained through virtual screening of an in-house compound database. Rate constant (kr) efficacy values of the non-oximes were found to be within ten-fold of pralidoxime (2-PAM) in an in vitro DFP inhibited eel AChE assay and one of them showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP induced neuropathology in guinea pigs. Short listing of the identified compounds were performed on the basis of in silico evaluations for favorable blood brain barrier penetrability, octanol-water partition (Clog P), toxicity (rat oral LD50) and binding affinity to the active site of the crystal structure of a OP- inhibited AChE.

In silico stereo-electronic analysis of PMD (p-Menthane-3-8-Diol) and its derivatives for pharmacophore development may aid discovery of novel insect repellents.

PMD (p-menthane-3-8-diol) is an insect repellent that can be synthesized chemically or derived from a steam distillate residue of the leaves of lemon eucalyptus, Corymbia citriodora. It is one of the few natural product endorsed by the Center for Disease Control (USA) for topical application to protect against mosquitoes though it is not as effective as the common repellent DEET (N,N -diethyl-1,3-toluamide). However, DEET has several undesirable side effects and toxicity too.

In silico pharmacophore modeling on known pyridinium oxime reactivators of cyclosarin (GF) inhibited AChE to Aid discovery of potential, more efficacious novel non-oxime reactivators.

Cyclohexyl methylphosphonofluoridate (cyclosarin, cyclosin, GF) is a highly toxic organophosphorus (OP) nerve agent considered as potential warfare threats and known to be resistant to conventional oxime antidotal therapy. To aid discovery of novel antidotes for GF toxicity, a three-dimensional in silico pharmacophore model for reactivation efficacy against GF intoxication is presented. The model was generated from published experimental percentage reactivation data on oximes as changes of AChE/BuChE activities in the whole blood after cyclosarin intoxication and administration.

Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods.

Muscarinic acetylcholine receptors (mAChRs) have five known subtypes which are widely distributed in both the peripheral and central nervous system for regulation of a variety of cholinergic functions. Atropine is a well known muscarinic subtype non-specific antagonist that competitively inhibits acetylcholine (ACh) at postganglionic muscarinic sites. Atropine is used to treat organophosphate (OP) poisoning and resulting seizures in the warfighter because it competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors.

An in silico stereo-electronic comparison of conventional pyridinium oximes and K-oximes for organophosphate (OP) poisoning.

A comparative analysis of stereo-electronic properties of five cholinesterase reactivators (pralidoxime (2- PAM), trimedoxime, obidoxime, HI-6, and HLo-7) and six "K-oximes" was performed to assess their roles in reactivating OP-inhibited phosphorylated serine residue of mouse AChE. Quantum mechanical (QM) calculations starting from semiempirical to ab initio levels were sequentially performed with hierarchical basis sets to obtain the individual optimized geometry and stereo-electronic properties of the eleven oximes. Next, solvation effects were computed on the optimized structures using two different (PCM and COSMO) QM models.

Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase.

We earlier reported an in silico pharmacophore model for reactivation of oximes to tabun-inhibited AChE. Since DFP (diisopropylfluorophosphate) like tabun is a G-agent simulator, we utilized the model as a rational strategy to discover non-oxime reactivators of DFP-inhibited AChE in this study. The phramacophore was used for virtual screening of two commercial databases, Maybridge and ChemNavigator, to identify reactivators which lack the oxime functions.

In vitro efficacy of 7-benzylamino-1-isoquinolinamines against Plasmodium falciparum related to the efficacy of chalcones.

A series of 1,7-diaminoisoquinolinamines, that are expected to mediate antimalarial activity by the same mechanism employed by the chalcones, were produced. Six 7-benzylamino-1-isoquinolinamines were found to be submicromolar inhibitors in vitro of drug-resistant Plasmodium falciparum, with the best possessing activity comparable to chloroquine. Despite being developed from a lead that is a DHFR inhibitor, these compounds do not mediate their antimalarial effects by inhibition of DHFR.

In silico pharmacophore model for tabun-inhibited acetylcholinesterase reactivators: a study of their stereoelectronic properties.

Organophosphorus (OP) nerve agents that inhibit acetylcholinesterase (AChE; EC 3.1.1.

Enhanced antibody responses to a detoxified lipopolysaccharide-group B meningococcal outer membrane protein vaccine are due to synergistic engagement of Toll-like receptors.

When given passively or elicited actively, antibodies induced by a detoxified Escherichia coli Rc chemotype (J5) mutant lipopolysaccharide (J5dLPS)-group B meningococcal outer membrane protein (OMP) complex vaccine protected animals from lethal sepsis. The protection from sepsis is believed to be dependent on high levels of antibodies against the core glycolipid (CGL), a region of LPS that is rather conserved among Enterobacteriaceae. The addition of unmethylated deoxycytidyl-deoxyguanosine dinucleotide (CpG)-containing oligodeoxynucleotides (ODN) was used as an immuno-adjuvant to improve antibody responses.

3D-QSAR studies of 2,2-diphenylpropionates to aid discovery of novel potent muscarinic antagonists.

Muscarinic acetylcholine receptors (mAChRs) consisting of five known subtypes, are widely distributed in both central and peripheral nervous systems for regulation of a variety of critical functions. The present theoretical study describes correlations between experimental and calculated molecular properties of 15 alpha-substituted 2,2-diphenylpropionate antimuscarinics using quantum chemical and pharmacophore generation methods to characterize the drug mAChR properties and design new therapeutics. The calculated stereoelectronic properties, such as total energies, bond distances, valence angles, torsion angles, HOMO-LUMO energies, reactivity indices, vibrational frequencies of ether and carbonyl moieties, and nitrogen atom proton affinity were found to be well correlated when compared with experimentally determined inhibition constants from the literature using three muscarinic receptor assays: [(3)H]NMS receptor binding, alpha-amylase release from rat pancreas, and guinea pig ileum contraction.

Intranasal administration of a detoxified endotoxin vaccine protects mice against heterologous Gram-negative bacterial pneumonia.

When given passively or elicited actively, antibodies induced by a detoxified Escherichia coli J5 mutant lipopolysaccharide (J5dLPS)-group B meningococcal outer membrane protein (-OMP) vaccine previously protected animals from lethal sepsis. To assess the use of this vaccine for the treatment of Gram-negative bacillary pneumonia, we vaccinated mice, with or without the adjuvant CpG, by intranasal (i.n.

In silico three-dimensional pharmacophores for aiding the discovery of the Pfmrk (Plasmodium cyclin-dependent protein kinases) specific inhibitors for the therapeutic treatment of malaria.

The resurgence of malaria and lack of effective antimalarial drugs affect millions of people worldwide every year, causing several million deaths. With the emergence of structure-based drug design methodologies, a major thrust in drug discovery efforts has shifted towards targeting specific proteins in parasites that are involved in their metabolic pathways. Although cyclin-dependent kinases (CDKs), due to their direct role in cell cycle regulations, have been targeted for the development of cancer therapeutics, CDKs for Plasmodium falciparum have only been recently identified to be attractive for the discovery of antimalarials.

Novel semi-automated methodology for developing highly predictive QSAR models: application for development of QSAR models for insect repellent amides.

Conventional 3D-QSAR models are built using global minimum conformations or quantum-mechanics based geometry-optimized conformations as bioactive conformers. QSAR models developed using the global minima as bioactive conformers, employing the GFA, PLS and G/PLS methodologies, gave good non-validated r(2) (0.898, 0.

Comparison of protective efficacy of subcutaneous versus intranasal immunization of mice with a Brucella melitensis lipopolysaccharide subunit vaccine.

Groups of mice were immunized either subcutaneously or intranasally with purified Brucella melitensis lipopolysaccharide (LPS) or with LPS as a noncovalent complex with Neisseria meningitidis group B outer membrane protein (LPS-GBOMP). Control mice were inoculated with sterile saline. Two doses of vaccine were given 4 weeks apart.

Identification of smooth and rough forms in cultures of Brucella melitensis strains by flow cytometry.

Brucella melitensis strains may occur as either smooth or rough variants depending on the expression of O-polysaccharides (OPS) as a component of the bacterial outer membrane lipopolysaccharide (LPS). The wboA gene, which codes for the enzyme glycosyl transferase, is essential for the assembly of O-chain in Brucella. Deletion of wboA in smooth virulent B.

Analysis of molecular stereoelectronic similarity between N,N-diethyl-m-toluamide (DEET) analogs and insect juvenile hormone to develop a model pharmacophore for insect repellent activity.

Similarity analysis on molecular stereoelectronic properties of N,N-diethyl-m-toluamide (DEET), natural insect juvenile hormone (JH), a synthetic insect juvenile hormone mimic (JH-mimic, undecen-2-yl carbamate), and DEET compounds reveals remarkable similarities that lead to a reliable pharmacophore for the design of efficacious insect repellents and provide insights for understanding the mechanism of repellent action. The study involves an AM1 quantum chemical computational procedure enabling a conformational search for the lowest and most abundant energy conformers of JH, JH-mimic, and 15 DEET compounds and complete geometry optimization of the conformers. Similarity analyses of stereoelectronic properties such as structural parameters, atomic charges, dipole moments, molecular electrostatic potentials, and highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were performed on JH, JH-mimic, and the DEET compounds.

In vitro and in vivo efficacy and in vitro metabolism of 1-phenyl-3-aryl-2-propen-1-ones against Plasmodium falciparum.

Investigation of a series of 1-phenyl-3-aryl-2-propen-1-ones resulted in the identification of nine inhibitors with submicromolar efficacy against at least one Plasmodium falciparum strain in vitro. These inhibitors were inactive when given orally in a Plasmodium berghei infected mouse model. Significant compound degradation occurred upon their exposure to a liver microsome preparation, suggesting metabolic instability may be responsible for the lack of activity in vivo.