Mohsin Y. Lone

Pharmacophore model prediction, 3D-QSAR and molecular docking studies on vinyl sulfones targeting Nrf2-mediated gene transcription intended for anti-Parkinson drug design.

Despite intense research efforts towards clinical and molecular causes of Parkinson disease (PD), the etiology of disease still remains unclear. However, recent studies have provided ample evidences that the oxidative stress is the key player that contributes a lot to dopaminergic (DAergic) neurodegeneration in brain. It is due to the discrepancy of antioxidant defence system of which nuclear factor erythroid 2-related factor 2 (Nrf2) signalling is of central contour. In the current study, potent heme oxygenase-1 agonists (Nrf2 signalling regulator), vinyl sulfones, were selected and an optimal pharmacophore model was brought forth which was examined using a decoy set by atom-based 3D-QSAR. The best four-feature model consists of two hydrogen bond acceptors and two aromatic rings, which has the highest correlation coefficient, R2 = .71 and = .73 in QSAR. These ligands were further studied for molecular docking with Nrf2-keap protein to gain insight into the major binding motifs followed by analysing pharmacokinetic properties to evaluate their bioavailability dominance. From this study, it is concluded that vinyl sulfones could be ideal compounds for targeting Nrf2 pathway which in turn halt the PD progression. Hence, these can be considered as potential leads for drug development against the same. Graphical abstract

Synthesis, Structure, and Optical Studies of Donor–Acceptor‐Type Near‐Infrared (NIR) Aza–Boron‐Dipyrromethene (BODIPY) Dyes

Six donor-acceptor-type near-infrared (NIR) aza-boron-dipyrromethene (BODIPY) dyes and their corresponding aza-dipyrrins were designed and synthesized. The donor moieties at the 1,7-positions of the aza-BODIPY core were varied from naphthyl to N-phenylcarbazole to N-butylcarbazole. The 3,5-positions were also substituted with phenyl or thienyl groups in the aza-BODIPYs. Photophysical, electrochemical, and computational studies were carried out. The absorption and emission spectra of aza-BODIPYs were significantly redshifted (≈100 nm) relative to the parent tetraphenylaza-BODIPY. Fluorescence studies suggested effective energy transfer (up to 93 %) from donor groups to the aza-BODIPY core in all of the compounds under study. Time-dependent (TD)-DFT studies indicated effective electronic interactions between energy donor groups and aza-dipyrrin unit in all the aza-BODIPYs studied. The HOMO-LUMO gap (ΔE) calculated from cyclic voltammetry data was found to be lower for six aza-BODIPYs relative to their corresponding aza-dipyrrins.

Identification of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase inhibitors: A combined in-silico and in-vitro analysis

Mycobacterium tuberculosis (Mtb), had developed evolutionary changes in its genome to adapt for survival and thereby generated multi-drug resistant strains. However, novel drug targets that remained unchanged for their biochemical role has impressed the research community to target such proteins. The comprehensive analysis of multiple protein targets has influenced us to make a consensus structural rule exploited by pharmacophore and other allied techniques from a large repository of protein structures. In this pursuit, we made a retrospective analysis of pharmacophores mapped from the tuberculosis structural proteome and identified unique patterns that can be employed for the novel molecules design. The current work on NADH-dependent enoyl-acyl carrier protein reductase (InhA) has yielded top scored pharmacophore models which were searched over SPECS natural product database to prioritize the molecules that can be targeted against Mtb. With efforts on rigorous validation and expertise, we have identified such pharmacophoric patterns from natural compounds that can be used as initial hits. Subsequently, these hits were subjected to in-vitro antitubercular evaluation to ensure the inhibitory activity against the mycobacterium culture growth (MtbH37Rv). Furthermore, docking simulations were carried out to provide an insight on the possible modes of interaction between the experimentally explored compounds and InhA.

Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies

In the present work, multiple pharmacophore-based virtual screening of the SPECS natural product database was carried out to identify novel inhibitors of the validated biological target, InhA. The pharmacophore models were built from the five different groups of the co-crystallized ligands present within the active site. The generated models with the same features from each group were pooled and subjected to the test set validation, receiver–operator characteristic analysis and Güner–Henry studies. A set of five hypotheses with sensitivity > 0.5, specificity > 0.5, area under curve (AUC) > 0.7, and goodness of hit score > 0.7 were retrieved and exploited for the virtual screening. The common hits (87 molecules) obtained from these hypotheses were processed via drug-likeness filters. The filtered molecules (27 molecules) were compared for the binding modes and the top scored molecules (12 molecules) along with the reference (triclosan (TCL), docking score = −11.65 kcal/mol) were rescored and reprioritized via molecular mechanics-generalized Born surface area approach. Eventually, the stability of reprioritized (10 molecules) docked complexes was scrutinized via molecular dynamics simulations. Moreover, the quantum chemical studies of the dynamically stable compounds (9 molecules) were performed to understand structural features essential for the activity. Overall, the protocol resulted in the recognition of nine lead compounds that can be targeted against InhA.

Multicomplex-based Pharmacophore Modeling Coupled with Molecular Dynamics Simulations: An Efficient Strategy for the Identification of Novel Inhibitors of Pf DHODH

Enormous efforts have been made in the past to identify novel scaffolds against the potential therapeutic target, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). Fourteen different organic molecules have been crystallized to understand the structural basis of the inhibition. However, the pharmacophoric studies carried out so far, have not exploited all the structural information simultaneously to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore hypotheses from the available PfDHODH structural proteome. Among the generated hypotheses, a representative hypothesis was employed as a primary filter to list the molecules with complimentary features accountable for inhibition. Moreover, the auxiliary evaluations of the filtered molecules were accomplished via docking and drug-likeness studies. Subsequently, the stability of the protein-ligand complex was evaluated by using molecular dynamics simulations (MDs). The molecular details of binding interactions of the potential hits were compared with the highly active experimental structure (5FI8) to seek the more potent candidates that can be targeted against PfDHODH. Overall, the combination of screening and stability procedures resulted in the identification of three potent candidates. The drug-likeness of these molecules lie within the acceptable range and consequently increased the opportunities for their development to new anti-malarials.

First protein drug target’s appraisal of lead-likeness descriptors to unfold the intervening chemical space

Despite the advances in combinatorial chemistry, high throughput and virtual screening experiments, plethora of clinical studies disquiet due to lead and drug-likeness attritions. For mitigation, the knowledge of physicochemical properties are really useful for guiding and selection of compounds from libraries dictated by certain rule of thumbs. However, robust bio-technological and instrumental innovations have created exponential increase in novel compounds and databases which compelled rethinking of the evaluation procedures. Known descriptive molecular property filters proposed by Lipinski, Verber and Hann are not efficient enough to encompass long array of compounds. Moreover, these filters do not take into account the specificity of biological target. In this pursuit, we have tried to appraise eight molecular properties for two major classes of biological targets viz membrane proteins and ion channels binding ligands. These molecular properties were utilized to search for the specific attributes that can be identified as an intervening space for dictating the biological activity.

Exploration of Mycobacterium tuberculosis structural proteome: An in-silico approach

Pharmacophore approaches are of central contour in drug discovery. However, the dependence of ligand-based pharmacophore model on appropriate training set molecules and typical use of apo-protein or single protein-ligand complex for the construction of structure-based pharmacophore models might skip some vital information. Therefore, multiple-complex based approach was employed for the construction of pharmacophore models of the Mycobacterium structural proteome. Moreover, the strategy of clustering of common pharmacophore hypotheses was made to gain an insight about the pharmacophore-similarity across the protein classes and share of features among the inhibitors. Rationale behind the present work was to present the scenario of virtual screening and guiding principle for designing efficient inhibitor by taking into account the available pharmacophoric space.

Corrosion inhibition and adsorption behaviour of black pepper extract on pure aluminum in hydrochloric acid medium

Purpose – The purpose of this paper is to investigate the inhibitive properties of black pepper extract (BPE) for aluminium in 1M hydrochloric acid (HCl) medium. Design/methodology/approach – Gravimetric, electrochemical impedance spectroscopy, galvanostatic polarization, scanning electron microscopy with energy dispersive X-ray examinations (SEM-EDX) techniques were used to study the corrosion inhibitive study. Findings – The gravimetric measurement indicates that inhibition efficiency shows direct proportional relation with concentration of inhibitor. The impedance results illustrates that there was a presence of protective layer of inhibitor adsorbed on the metal/solution interface. Polarization outcome showed that BPE is mixed type inhibitor. The existence of adherent layer of inhibitor on the Al surface was confirmed by SEM-EDX. Quantum chemical calculations were performed using the density functional theory at B3LYP/6-31G(d) level of theory to evaluate the activity of inhibitor molecules present in ...

Prioritization of natural compounds against mycobacterium tuberculosis 3-dehydroquinate dehydratase: A combined in-silico and in-vitro study

Enormous efforts have been endeavored to develop inhibitors against the potential therapeutic target, mycobacterium tuberculosis 3-dehydroquinate dehydratase (MtbDHQase) to combat resistance. Over a dozen of small molecules have been crystallized to characterize the structural basis of the inhibition. However, the studies accomplished so far, have not incorporated all the essential interactions of these complexes simultaneously, to identify the novel inhibitors. Therefore, an attempt was made to construct the pharmacophore models and identify the essential features that can be employed to prioritize the molecules against this target. Based on validation and expertise, we have identified such complimentary features from the natural compounds that can be used as initial hits. Subsequently, these hits were tested for their inhibitory roles in reducing the mycobacterium tuberculosis (Mtb) culture growth. Moreover, the docking simulations were performed to seek the possible interactions accountable for the activity of these candidates against MtbDHQase.

In search of the representative pharmacophore hypotheses of the enzymatic proteome of Plasmodium falciparum: a multicomplex-based approach

Drug resistance has made malaria an untreatable disease and therefore intensified the need for the development of new drugs and the identification of potential drug targets. In this pursuit, in silico efforts made in the past have not shown significant responses. Therefore, in the present work, the multicomplex-based pharmacophore modeling approach was employed to construct the pharmacophores of the 16 selected Plasmodium falciparum (Pf) targets. All the constructed hypotheses (153) were screened against a focused dataset made up of experimental actives of the chosen targets (3705 inhibitors). The rationale was to check the affinity of the inhibitors for the off-targets. Subsequently, the constructed hypotheses from each target were pooled based on the feature types and the pooled-hypotheses were then clustered to offer an insight about the pharmacophore similarity. Tanimoto similarity index was also calculated to look for the similarity among the inhibitors belonging to different Pf targets. Overall, the work was accomplished to bid healthier perceptive of the pharmacophore-based virtual screening and abet in providing guiding principles for the construction of stringent pharmacophores that can be employed for the screening.Graphical abstract