QSAR Studies to Predict Activity of HSP90 Inhibitors.

Heat shock protein 90 (HSP90) is a multichaperone complex that mediates the maturation and stability of a variety of oncogenic signaling proteins. HSP90 has emerged as a promising target for the development of anticancer agents. Heterocyclic chemical moieties with HSP90 inhibitory activity were studied continuously during the last decades, and resulting data were applied by medicinal chemists to design and develop new drugs. Their structure-activity relationship (SAR) studies and QSAR models have been derived to assist the current drug development process. The QSAR models are obtained via multiple linear regression (MLR) and non-linear approaches. Interpretation of the reported model highlights the core template required to design novel, potent HSP90 inhibitors to be used as anticancer agents.

In-silico Studies and Biological Activity of Potential BACE-1 Inhibitors.

BACKGROUND: Alzheimer's disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). OBJECTIVE: The controlled APP processing by inhibition of secretase is the strategy to reduce Aß load to treat Alzheimer's disease. METHODS: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds. RESULTS: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions. CONCLUSION: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1µM.

Molecular Processes Exploited as Drug Targets for Cancer Chemotherapy.

Cancer is an uncontrolled malignant tumor growth taking place in any tissue of the body and attains complex diversity which makes it difficult for oncologists to choose therapeutics. The changes leading to formation of cancerous cells occur due to a series of molecular events. Now scientists are trying to understand the various molecular processes that are involved in the growth of cancers. This article presents a brief account of epigenetics with reference to DNA methylation and histone modification as an important contributor to the formation of cancer cells. Drug targeting the epigenetic regulators has been considered for various types of cancer. The enzymes in DNA methylation and histone modification, FDA approved clinical drugs along with the challenges associated with the development of anti-cancer target based therapeutics are summarized.

An Overview of Ovarian Cancer: Molecular Processes Involved and Development of Target-based Chemotherapeutics.

Ovarian cancer is one of the leading gynecologic diseases with a high mortality rate worldwide. Current statistical studies on cancer reveal that over the past two decades, the fifth most common cause of death related to cancer in females of the western world is ovarian cancer. In spite of significant strides made in genomics, proteomics and radiomics, there has been little progress in transitioning these research advances into effective clinical administration of ovarian cancer. Consequently, researchers have diverted their attention to finding various molecular processes involved in the development of this cancer and how these processes can be exploited to develop potential chemotherapeutics to treat this cancer. The present review gives an overview of these studies which may update the researchers on where we stand and where to go further. The unfortunate situation with ovarian cancer that still exists is that most patients with it do not show any symptoms until the disease has moved to an advanced stage. Undoubtedly, several targets-based drugs have been developed to treat it, but drug-resistance and the recurrence of this disease are still a problem. For the development of potential chemotherapeutics for ovarian cancer, however, some theoretical approaches have also been applied. A description of such methods and their success in this direction is also covered in this review.

Progress in Studies on Structural and Remedial Aspects of Newly Born Coronavirus, SARS-CoV-2.

The article highlights an up-to-date progress in studies on structural and the remedial aspects of novel coronavirus 2019-nCoV, renamed as SARS-CoV-2, leading to the disease COVID-19, a pandemic. In general, all CoVs including SARS-CoV-2 are spherical positive single-stranded RNA viruses containing spike (S) protein, envelope (E) protein, nucleocapsid (N) protein, and membrane (M) protein, where S protein has a Receptor-binding Domain (RBD) that mediates the binding to host cell receptor, Angiotensin Converting Enzyme 2 (ACE2). The article details the repurposing of some drugs to be tried for COVID-19 and presents the status of vaccine development so far. Besides drugs and vaccines, the role of Convalescent Plasma (CP) therapy to treat COVID-19 is also discussed.

Recent Studies on Design and Development of Drugs Against Alzheimer's Disease (AD) Based on Inhibition of BACE-1 and Other AD-causative Agents.

BACKGROUND: Alzheimer's disease (AD) is one of the neurodegenerative diseases and has been hypothesized to be a protein misfolding disease. In the generation of AD, ß-secretase, γ-secretase, and tau protein play an important role. A literature search reflects ever increasing interest in the design and development of anti-AD drugs targeting ß-secretase, γ-secretase, and tau protein. OBJECTIVE: The objective is to explore the structural aspects and role of ß-secretase, γ-secretase, and tau protein in AD and the efforts made to exploit them for the design of effective anti-AD drugs. METHODS: The manuscript covers the recent studies on design and development of anti-AD drugs exploiting amyloid and cholinergic hypotheses. RESULTS: Based on amyloid and cholinergic hypotheses, effective anti-AD drugs have been searched out in which non-peptidic BACE1 inhibitors have been most prominent. CONCLUSION: Further exploitation of the structural aspects and the inhibition mechanism for ß-secretase, γ-secretase, and tau protein and the use of cholinergic hypothesis may lead still more potent anti-AD drugs.

Quantum Molecular Dynamics, Topological, Group Theoretical and Graph Theoretical Studies of Protein-Protein Interactions.

BACKGROUND: Protein-protein interactions (PPIs) are becoming increasingly important as PPIs form the basis of multiple aggregation-related diseases such as cancer, Creutzfeldt-Jakob, and Alzheimer's diseases. This mini-review presents hybrid quantum molecular dynamics, quantum chemical, topological, group theoretical, graph theoretical, and docking studies of PPIs. We also show how these theoretical studies facilitate the discovery of some PPI inhibitors of therapeutic importance. OBJECTIVE: The objective of this review is to present hybrid quantum molecular dynamics, quantum chemical, topological, group theoretical, graph theoretical, and docking studies of PPIs. We also show how these theoretical studies enable the discovery of some PPI inhibitors of therapeutic importance. METHODS: This article presents a detailed survey of hybrid quantum dynamics that combines classical and quantum MD for PPIs. The article also surveys various developments pertinent to topological, graph theoretical, group theoretical and docking studies of PPIs and highlight how the methods facilitate the discovery of some PPI inhibitors of therapeutic importance. RESULTS: It is shown that it is important to include higher-level quantum chemical computations for accurate computations of free energies and electrostatics of PPIs and Drugs with PPIs, and thus techniques that combine classical MD tools with quantum MD are preferred choices. Topological, graph theoretical and group theoretical techniques are shown to be important in studying large network of PPIs comprised of over 100,000 proteins where quantum chemical and other techniques are not feasible. Hence, multiple techniques are needed for PPIs. CONCLUSION: Drug discovery and our understanding of complex PPIs require multifaceted techniques that involve several disciplines such as quantum chemistry, topology, graph theory, knot theory and group theory, thus demonstrating a compelling need for a multi-disciplinary approach to the problem.

N-Substituted Aryl Sulphonamides as Potential Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation.

INTRODUCTION: A novel series of multifunctional anti-Alzheimer's agents based on Nsubstituted aryl sulphonamides were designed and synthesized. During in vivo moderate to good anti- Alzheimer's Disease (AD) activity was observed as correlated by the modulation of some selected biochemical markers of AD as well as during behavioral assessment. METHODS: Among the series, some compounds have shown multi-functional potency by inhibition of Acetylcholinesterase (AChE), Scopolamine induced oxidative stress and were found comparable to the standard drug. Successful modulation of biochemical markers of oxidative stress in AD, displays neuroprotective properties and did not exert any significant toxicity. RESULTS AND CONCLUSION: Thus, the present study has evidently shown that these series of compounds have potential to be optimized as anti-AD agents with multi-functional properties. The aryl sulphonamide nucleus might serve as a promising lead candidate for developing novel anti-AD drug.

Designing of Selective γ-Secretase Inhibitory Benzenesulfonamides through Comparative In Vitro and In Silico Analysis.

BACKGROUND: In Alzheimer's disease (AD), the gene mutations have been identified in the amyloid precursor protein (APP), the presenilin-1 (PS1) and -2 (PS2) genes. APP is a transmembrane protein which gets cleaved by α- and ß- secretase enzymes and releases Aß peptides which forms senile plaques in brain tissue. It contributes for local inflammatory response, subsequent oxidative stress, biochemical changes and neuronal death. Targeting the development of Aß aggregates in the senile plaques is an important strategy in the treatment of AD. To facilitate the normal processing of APP, some of the reported approaches are stimulation of α- secretase activity or the modulation/inhibition of the ß- and γ-secretase complex. METHODS: The mechanism of γ-secretase inhibition is targeted based on the QSAR and molecular docking methods. The series based on 3-chloro-2-hydroxymethylbenzenesulfonamide was selected for in silico ligand-based modeling. Significant correlations, between their γ-Secretase inhibitory profile and 2D-descriptors, were obtained through multiple linear regression (MLR) computational procedure. RESULTS: During QSAR nalysis, calculated molar refractivity (CMR) and surface tension (ST) were found to be contributing parameters along with halogen substituent at a particular position. Applicability analysis revealed that the suggested models have acceptable predictability (rpred2 = 0.827). CONCLUSION: The inferences drawn from MLR were utilized to prepare a data set of fourteen substituted benzenesulfonamides (N1-N14). The in silico studies provides strong impetus towards systematic application of such methods during lead identification and optimization.

GENIUS In Silico Screening Technology for HCV Drug Discovery.

The various reported in silico screening protocols such as molecular docking are associated with various drawbacks as well as benefits. In molecular docking, on interaction with ligand, the protein or receptor molecule gets activated by adopting conformational changes. These conformational changes cannot be utilized to predict the 3D structure of a protein-ligand complex from unbound protein conformations rigid docking, which necessitates the demand for understanding protein flexibility. Therefore, efficiency and accuracy of docking should be achieved and various available/developed protocols may be adopted. One such protocol is GENIUS induced-fit docking and it is used effectively for the development of anti-HCV NS3-4A serine protease inhibitors. The present review elaborates the GENIUS docking protocol along with its benefits and drawbacks.

Studies on Chloride Channels and their Modulators.

The prime roles of mutations in the genes, encoding chloride ion channels, in various human diseases of muscle, kidney, bone and brain, such as congenital myotonia, myotonic dystrophy, cystic fibrosis, osteopetrosis, epilepsy, glioma, etc., have been well established. Chloride ion channels are also responsible for glioma progression in brain and malaria parasite in red blood cells. The present article thus emphasises on the various diseases associated with chloride channel regulation and their modulators. Studies on various chloride channels and their modulators have been discussed in detail.

Heterocyclic Secretase Inhibitors for the Treatment of Alzheimer's Disease: An Overview.

Alzheimer's disease (AD), the most common neurodegenerative disorder and demands to find a way for prevention and delayed onset. The development of therapeutics for AD is based on the amyloid cascade hypothesis (vaccines, ß- and γ-Secretase inhibitors), or targeting tau and neurofibrillary tangle formation, neuroinflammation, etc. Cholinesterase, BACE-1, amyloid-ß 1-42, γ and ß-Secretase, Phosphodiesterase type IV (PDE4) inhibitors are the reported treatment strategies. Among these, the γ- and ß-Secretase inhibitors can be clustered in several heterocyclic classes (imidazoles, thiazoles, indoles, benzaldehydes, pyrimidine, etc), with subsequent description of the structure-activity relationships, and extended to the pharmacological profile in order to evaluate their drug-likeness, with special attention to toxicity and bioavailability. This article discusses the approaches proposed by several research groups working on the synthesis of enzyme inhibitors, based on modelling studies and the way these findings were used to obtain new drugs for the treatment of AD.

A comparative 2D QSAR study on a series of hydroxamic acid-based histone deacetylase inhibitors vis-à-vis comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

A quantitative structure-activity relationship (QSAR) study was performed on a series of indole amide analogues reported by Dai et al. [Bioorg Med Chem Lett (2003), 13, 1897-1901] to act as histone deacetylase (HDAC) inhibitors. The multiple regression analysis (MRA) revealed a model showing the significant dependence of the activity on molar refractivity (MR) and global topological charge index (GTCI) of the compounds, suggesting that inhibition of the HDAC by this series of compounds might involve the dispersion interaction with the receptor, where charge transfer between pairs of atoms might greatly help to polarize the molecule. The MRA results were then compared with those obtained by Guo et al. [Bioorg Med Chem (2005), 13, 5424-5434] by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). It was found that MRA gave as good results and had as good predictive ability as CoMFA and CoMSIA. Besides, MRA was also able to throw the light on the physicochemical properties of the molecules that were involved in drug-receptor interactions, while CoMFA and CoMSIA could not. The dispersion interaction between the molecule and the active site of the receptor is suggested to be the main interaction.

A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase.

QSAR study was performed on a series of 1,2-dihydro-4-quinazolinamines, 4,5-dialkylsubstituted-2-imino-1,3-thiazolidine derivatives and 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives studied by Tinker et al. [J Med Chem (2003), 46, 913-916], Ueda et al. [Bioorg Med Chem (2004) 12, 4101-4116] and Ueda et al. [Bioorg Med Chem Lett (2004) 14, 313-316], respectively, as potent, highly selective inhibitors of inducible nitric oxide synthase (iNOS). The iNOS inhibition activity of the whole series of compounds was analyzed in relation to the physicochemical and molecular properties of the compounds. The QSAR analysis revealed that the inhibition potency of the compounds was controlled by a topological parameter 1chi(v) (Kier's first order valence molecular connectivity index), density (D), surface tension (St) and length (steric parameter) of a substituent. This suggested that the drug-receptor interaction predominantly involved the dispersion interaction, but the bulky molecule would face steric problem because of which the molecule may not completely fit in active sites of the receptor and thus may not have the optimum interaction.

A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Heteroaryl- and Heterocyclyl-Substituted Imidazo[1,2-a]Pyridine Derivatives Acting as Acid Pump Antagonists.

A quantitative structure-activity relationship (QSAR) and molecular docking study has been performed on a series of heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine derivatives acting as acid pump antagonists in order to have a better understanding of the mechanism of H(+)/K(+)-ATPase inhibition. The QSAR study shows a significant correlation of activity with Global Topological Charge Indices (GTCI) of the compounds and the hydrophobic constant π of some substituents, indicating that the charge transfer within the molecule and the hydrophobic property of some substituents will be the controlling factor of the activity of these compounds and that there can be dispersion interaction between the molecules and the receptor, where some substituents may have hydrophobic interaction, too. Based on this correlation some new compounds with higher potency have been predicted and their docking study has been performed to see if they can have better interaction with the receptor. The ADME properties of these predicted compounds have also been reported that follow Lipinski's rule of five.

A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors.

A quantitative structure-activity relationship (QSAR) and molecular modeling study were performed on a series of 3,4-dihyro-1-isoquinolinamines and thienopyridines reported by Beaton et al. [Beaton et al. (2001) Bioorg Med Chem Lett 11, 1023-1026, 1027-1030] as potent, highly selective inhibitors of two isoforms of nitric oxide synthase (NOS)--neuronal NOS (nNOS) and endothelial NOS (eNOS), in order to find the physicochemical properties that governed their activity and the mode of interaction with the receptors, so that still more potent compounds in the series could be suggested. A multiple regression analysis revealed that nNOS and eNOS inhibition potency of these compounds could be controlled by their hydrophobic property and molar refractivity, respectively. Thus, nNOS and eNOS inhibition was indicated to involve the hydrophobic interaction and steric effects, respectively, suggesting some structural differences of the two isoforms of NOS. Based on the correlations obtained, some new, more potent compounds belonging to the series were predicted. These compounds were then docked into the receptors to see their interactions and find out the docking scores. The docked structures of two representative compounds, whose interaction energies with nNOS and eNOS, respectively were found to be the lowest, were given as an example to exhibit the possible orientation of the compounds to interact with the receptors.