Molecular diversity in the context of leadlikeness: compound properties that enable effective biochemical screening

Molecular diversity is of vital importance in drug screening in general and for the discovery and development of new pharmacophores in particular. Biochemical screening is a powerful tool for pharmacophore development given understanding of the properties of a good lead compound operating in the biochemical environment. The properties of leadlikeness have evolved to accommodate the artificial conditions of a biochemical assay. Accordingly, the properties of leadlikeness that are suited for screening at protein targets biochemically are different and complementary to the properties of druglikeness used to guide the selection of good compounds studied biologically in cellular studies and animal models. The benefits of leadlikeness in the biochemical screening arena (including fragment-based screening and co-crystallization studies) are described here and recommendations are forwarded for the generation of leadlike molecular diversity. Chemically stable low molecular weight 'minimalist' compounds (or fragments) with dense heteroatom substitution and variable conformational constraint are promoted as conceptually superior compounds for biochemical screening.     

Quantum chemical studies of the metabolism of polycyclic aromatic amines and the stabilities and electrophilicities of their arylnitrenium ions in relation to their mutagenic/carcinogenic potencies.

Electronic parameters related to the cytochrome P450-catalyzed reactions of eight polycyclic aromatic amines have been calculated using all valence electron semiempirical molecular orbital methods. The reactions considered lead to the presumably carcinogenic arylnitrenium ions and to the competing hydroxylation and epoxidation products. The stabilities of the arylnitrenium ions relative to the N-hydroxylamines and their sulfate esters were also calculated, together with electrophilic reactivity parameters of the ions. The resulting parameters were used to predict major metabolites of the parent compounds and also to correlate with observed mutagenic activities of the four pairs of polycyclic aromatic amines studied. The major factor in determining mutagenic potencies of parent compounds appears to be the extent of N-hydroxylation and competing ring oxidations, as well as the electrophilic properties of the arylnitrenium ions.     

Biotechnological approaches to the understanding and improvement of mature cheese flavour

There have been important milestones in biotechnological practice that have led to the determination and production of superior cheese flavours. Within the past year, the use of gas chromatographic techniques and sensory methodologies has been optimised by several groups in efforts to evaluate the organoleptic properties of a number of mature cheeses. The hydrolysis of milk caseins, small peptides, free amino acids and fatty acids, and the generation of sulfur-containing compounds are uniformly assumed to result in the formation of specific cheese aromas. Giant strides have been taken in molecular technology to aid the dissection and exploitation of the metabolic pathways that lead to the formation of these flavour constituents. Specific advances in molecular technology have included metabolic engineering of lactic acid bacteria for enhanced flavour development.     

Deep understanding of structure-solubility relationship for a diverse set of organic compounds using matched molecular pairs

Aqueous solubility is an important biopharmaceutical property in drug discovery and development. Although it has been studied for decades, the impact on solubility by the substructures (or fragments) of compounds are still not fully understood and characterized. This study aims to obtain fragment-solubility relationships using matched molecular pairs, and to provide further insight and suggestions for chemists on structural modifications to improve solubility profiles of drug-like molecules. A set of 2794 compounds with measured intrinsic aqueous solubility (logS) was fragmented into rings, linkers, and R groups using a controlled hierarchical fragmentation method. Then matched molecular pairs that differ by only one chemical transformation (i.e., addition or substitution of fragments) were identified and analyzed. The difference in solubility for each matched molecular pair was calculated, and the impact of the corresponding chemical transformation on solubility was investigated. The final product of this study was a fragment-solubility knowledgebase containing relative contributions to solubility of various medicinal chemistry design elements (R-groups, linkers, and rings). Structural modifications that might improve solubility profiles, that is, addition/deletion/substitution of fragments, could be derived from this knowledgebase. This knowledgebase could be used as an expert tool in lead optimization to improve solubility profiles of compounds, and the analysis method could be applied to study other biological and ADMET properties of organic compounds.     

Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques

Acetylcholinesterase (AChE) is considered to be one of the most important targets for the treatment of Alzheimer's disease (AD). Previously our group has reported a series of tacrine-based hybrids as potent AChE inhibitors (AChEI). To discover more novel scaffolds, molecular docking and dynamics stimulation were applied to acquire the binding models of AChE with the most prominent compounds from our work. A structure-based pharmacophore model plus shape constraints was generated from the binding models and it was then employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored the hit compounds by their molecular binding energies, which were calculated by MM/PBSA method. Fifteen compounds were selected and purchased for testing their anti-AChE effects, while seven of them showed inhibitory effects with IC(50) values ranging from 1.5 to 9.8 μM. The drug-like properties of these compounds, including LogD, AlogP, molecular volume and Lipinski rule of five, were also calculated. Compounds 12 and 16 (IC(50)=2.5 and 1.5 μM, respectively) exhibited potent activity and acceptable drug-like properties, thus might serve as leads for further modification. The data suggest that the presented model might be a valid approach for identification and development of new AChEIs.     

计算机虚拟筛选技术在害虫行为调节剂研究中的应用

害虫行为调节剂是一种以嗅觉系统为靶标的绿色农药,在害虫的田间管理中发挥着重要的作用。然而,其先导化合物的发现通常依赖一系列生物测定的方法,不仅费时费力,且发现效率低。近年来,随着昆虫嗅觉功能数据的积累和结构生物学的飞速发展,以机器学习技术和分子对接为代表的2种基于计算机的药物虚拟筛选方法在害虫行为调节剂的先导化合物研究中发挥着重要的作用,极大地促进了先导化合物的发现效率,减少了筛选的盲目性。本文系统综述了2种虚拟筛选方法及其在害虫行为调节剂先导化合物研究中的应用,并对2种筛选策略在实际应用中存在的问题及应用前景进行了讨论。     

Natural compounds as a source of protein tyrosine phosphatase inhibitors: application to the rational design of small-molecule derivatives

Reversible phosphorylation of tyrosine residues is a key regulatory mechanism for numerous cellular events. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) have a pivotal role in regulating both normal cell physiology and pathophysiology. Accordingly, deregulated activity of both protein tyrosine kinases and PTPs is involved in the development of numerous congenitically inherited and acquired human diseases, prompting obvious pharmaceutical and academic research interest. The development of compound libraries with higher selective PTP inhibitory activity has been bolstered by the realization that many natural products have such activity and thus are interesting biologically lead compounds, which properties are widely exploited. In addition, more rational approaches have focused on the incorporation of phosphotyrosine mimetics into specific peptide templates (peptidomimetic backbones). Additional factors furthering discovery as well as therapeutic application of new bioactive molecules are the integration of functional genomics, cell biology, structural biology, drug design, molecular screening and chemical diversity. Together, all these factors will lead to new avenues to treat clinical disease based on PTP inhibition.     

Using Molecular Dynamics to Predict Factors Affecting Binding Strength and Magnetic Relaxivity of MRI Contrast Agents

We demonstrate the use of molecular dynamics and molecular mechanics methods to calculate properties and behavior of metal-chelate complexes that can be used as MRI contrast agents. Static and dynamic properties of several known agents were calculated and compared with experiment. We calculated the static properties such as the q-values (number of inner shell waters) and binding distances of chelate atoms to the metal ion for a set of chelates with known X-ray structure. The dynamic flexibility of the chelate arms was also calculated. These computations were extended to a series of exploratory chelate structures in order to estimate their potential as MRI contrast agents. We have also calculated for the first time the NMR relaxivity of an MRI contrast agent using a long (5 nsec) molecular dynamics simulation. Our predictions are promising enough that the method should prove useful for evaluating novel candidate compounds before they are synthesized. One novel static property, the projected area of chelate atoms onto a virtual surface centered on the metal ion (gnomonic projection), was found to give an effective measure of how well the chelate atoms use the free space around the metal ion.     

Antioxidant mechanisms of Quercetin and Myricetin in the gas phase and in solution – a comparison and validation of semi-empirical methods

Flavonoids have long been recognized for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work we have studied the properties of two flavonols, quercetin and myricetin, using semi-empirical methods in order to validate the application of the recent Parametric Model 6 and to understand the fundamental difference between the two molecules. Their geometries have been optimized and important molecular properties have been calculated. The energetic of the possible antioxidant mechanisms have also been analyzed. The two studied flavonols do not differ significantly in their molecular properties, but the antioxidant mechanisms by which they may act in solution can be rather different. Moreover, we also show that the Parametric Model 6 can produce reliable information for this type of compounds.     

Identification of Potential Inhibitors of H5N1 Influenza A Virus Neuraminidase by Ligand-Based Virtual Screening Approach

The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases were reported that influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. In this report, a novel class of lead molecule with potential NA inhibitory activity was identified using a combination of virtual screening (VS), molecular docking, and molecular dynamic approach. The PubChem database was used to perform the VS analysis by employing oseltamivir as query. Subsequently, the data reduction was carried out by employing molecular docking study. Furthermore, the screened lead molecules were analyzed with respect to the Lipinski rule of five, drug-likeness, toxicity profiles, and other physico-chemical properties of drugs by suitable software program. Final screening was carried out by normal mode analysis and molecular dynamic simulation approach. The result indicates that CID 25145634, deuterium-enriched oseltamivir, become a promising lead compound and be effective in treating oseltamivir sensitive as well as resistant influenza virus strains.     

Theoretical studies on the interaction between the nitrile-based inhibitors and the catalytic triad of Cathepsin K

Computational studies on the interaction of novel inhibitor compounds with the Cathepsin K protease have been performed to study the inhibition properties of the inhibitor compounds. The quantum chemical calculations have been performed to analyze the molecular geometries, structural stability, reactivity, nature of interaction, and the charge transfer properties using B3LYP level of theory by implementing 6-311g(d,p) basis set. The calculated C–S and N–H…N bond lengths of the inhibitor-triad complexes are found to agree well with the previous literature results. The chemical reactivity of the inhibitors and catalytic triad are analyzed through frontier molecular orbital analysis and found that the inhibitors are subjected to nucleophilic attack by the catalytic triad. The nature of inhibition of the inhibitor compounds is examined using the quantum theory of Atoms in Molecules analysis and found to be partially covalent. The NBO stabilization energy for the Cys – inhibitor are found to be most stable than the other interactions. The molecular dynamic simulations were performed to study the influence of dynamic of the active site on the QM results. The many body decomposition interaction energy calculated for the final results of MD simulation reveals that the dynamic of the active site induces significant changes in the interaction energy and occupancy of H-bonds plays a major role in the stabilizing the active site inhibitor interactions. The present study reveals that the inhibitor compounds can inhibit the proteolytic activity of the proteases on binding with the catalytic active site.     

Structure-activity relationship study of flavone compounds with anti-HIV-1 integrase activity: a density functional theory study

Human immunodeficiency virus type-1 integrase (HIV-1 IN) is an essential enzyme for effective viral replication. Flavone compounds have been very much studied due to their activity during the inhibition process of HIV-1 IN. In this study, we employed density functional theory (DFT) using the B3LYP hybrid functional to calculate a set of molecular properties for 32 flavonoid compounds with anti-HIV-1 IN activity. The stepwise discriminant analysis (SDA), principal component analysis (PCA) and hierarchical cluster analysis (HCA) methods were employed to reduce dimensionality and investigate possible relationship between the calculated properties and the anti-HIV-1 IN activity. These analyses showed that the molecular hydrophobicity (ClogP), charge on atom 11 and electrophilic index (omega) are responsible for the separation between anti-HIV-1 IN active and inactive compounds.     

Identification of Potential Carbonic Anhydrase Inhibitors for Glaucoma Treatment Through an In-Silico Approach

Glaucoma is a neurodegenerative disease and second leading cause of blindness in western world. The disease is characterized by an elevated intraocular pressure. Carbonic anhydrase plays a major role by forming aqueous humor and its inhibition can reduce intraocular pressure by partially suppressing the secretion of aqueous humor. Thus in this study, we proposed to identify the potential novel compounds targeting the carbonic anhydrase. The diversity set-II molecules library consisting of 1880 compounds from National Cancer Institute were virtually screened (molecular docking) against human carbonic anhydrase protein. For the obtained best compounds, the nature of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), which determine nucleophilic and electrophilic activity, were calculated by using density functional theory (DFT). The in silico screening suggested 5 best compounds that are effective in comparison to the dorzolamide, a widely used carbonic anhydrase inhibitor for glaucoma treatment. Of the five compounds, 4-nitro-7-[(1-oxidopyridin-1-ium-2-yl) thio] benzofurazan (ZINC01757986) exhibited the better binding affinity (??9.2 cal/mol) in comparison to dorzolamide (??7.2 kcal/mol). The DFT studies on novel identified compound, ZINC01757986 exhibited less HOMO–LUMO energy gap, low hardness and more softness (0.2305 eV, 0.1152 eV and 8.6805 eV) when compared to dorzalamide (0.9536 eV, 0.4768 eV and 2.0973 eV). These studies emphasize that ZINC01757986 can be used as potential carbonic anhydrase inhibitor and lead compounds for the development of an effective anti-glaucoma drug. The results emphasize that these compounds could be potential lead molecules for further structure-based discovery of antiglaucoma drugs.

     

Synthetic medicinal chemistry of selected antimalarial natural products

Natural products remain a rich source of novel molecular scaffolds for novel antimalarial agents in the fight against malaria. This has been well demonstrated in the case of quinine and artemisinin both of which have served as templates for the development of structurally simpler analogues that either served or continue to serve as effective antimalarials. This review will expound on these two natural products as well as other selected natural products that have served either as antimalarial agents or as potential lead compounds in the development of antimalarial drugs.     

Synthesis and biological evaluation of aromatic enones related to curcumin

Curcumin, a natural product isolated from the spice turmeric, has been shown to exhibit a wide range of pharmacological activities including certain anti-cancer properties. It has been specifically shown to be an effective inhibitor of angiogenesis both in vitro and in vivo. Using curcumin as a lead compound for anti-angiogenic analog design, a series of structurally related compounds utilizing a substituted chalcone backbone have been synthesized and tested via an established SVR cell proliferation assay. The results have yielded a wide range of compounds that equal or exceed curcumin's ability to inhibit endothelial cell growth in vitro. Due to both their commercial availability and their fairly straightforward synthetic preparation, these low molecular weight compounds are attractive leads for developing future angiogenic inhibitors.     

Ligand-Guided Investigation of a Series of Formamidine-Based Thiuram Disulfides as Potential Dual-Inhibitors of COX-1and COX-2

A series of thiuram disulfides 1–6 which had been previously synthesized and characterized,^[1] were studied for their potential therapeutic properties. Target-fishing analyses through HitPick and SwissTarget prediction identified COX1 and COX2, which are essential biomolecules in cancer-related inflammations, as the possible targets for compounds 1 and 4 among all the compounds tested. These two proteins have enjoyed interest as targets for treating some neoplastic cancer types such as breast, colorectal, skin, pancreatic, haematological and head cancers. The inhibitory potency of 1 and 4 as lead anticancer drug candidates with dual-target ability against COX1 and COX2 was examined through molecular docking, molecular dynamics simulation and post-MD analyses such as binding energy calculation, RMSD, RMSF, and RoG. The two compounds had better docking scores and binding energies than the known inhibitors of COX1 and COX2. Insights from the RMSD, RMSF, and RoG suggested that both 1 and 4 showed observable influence on the structural stability of these targets throughout the simulation. The reported observations of the effects of 1 and 4 on the structures of COX1 and COX2 indicate their probable inhibitory properties against these target proteins and their potential as lead anticancer drug candidates.     

Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A

Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity.Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.