Amir Zeb

Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria

Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinskis rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.

Exploration for novel inhibitors showing back-to-front approach against VEGFR-2 kinase domain (4AG8) employing molecular docking mechanism and molecular dynamics simulations

BackgroundAngiogenesis is a process of formation of new blood vessels and is an important criteria demonstrated by cancer cells. Over a period of time, these cancer cells infect the other parts of the healthy body by a process called progression. The objective of the present article is to identify a drug molecule that inhibits angiogenesis and progression.MethodsIn this pursuit, ligand based pharmacophore virtual screening was employed, generating a pharmacophore model, Hypo1 consisting of four features. Furthermore, this Hypo1 was validated recruiting, Fischer’s randomization, test set method and decoy set method. Later, Hypo1 was allowed to screen databases such as Maybridge, Chembridge, Asinex and NCI and were further filtered by ADMET filters and Lipinski’s Rule of Five. A total of 699 molecules that passed the above criteria, were challenged against 4AG8, an angiogenic drug target employing GOLD v5.2.2.ResultsThe results rendered by molecular docking, DFT and the MD simulations showed only one molecule (Hit) obeyed the back-to-front approach. This molecule displayed a dock score of 89.77, involving the amino acids, Glu885 and Cys919, Asp1046, respectively and additionally formed several important hydrophobic interactions. Furthermore, the identified lead molecule showed interactions with key residues when challenged with CDK2 protein, 1URW.ConclusionThe lead candidate showed several interactions with the crucial residues of both the targets. Furthermore, we speculate that the residues Cys919 and Leu83 are important in the development of dual inhibitor. Therefore, the identified lead molecule can act as a potential inhibitor for angiogenesis and progression.

Targeting natural compounds against HER2 kinase domain as potential anticancer drugs applying pharmacophore based molecular modelling approaches

Human epidermal growth factor receptors are implicated in several types of cancers characterized by aberrant signal transduction. This family comprises of EGFR (ErbB1), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4). Amongst them, HER2 is associated with breast cancer and is one of the most valuable targets in addressing the breast cancer incidences. For the current investigation, we have performed 3D-QSAR based pharmacophore search for the identification of potential inhibitors against the kinase domain of HER2 protein. Correspondingly, a pharmacophore model, Hypo1, with four features was generated and was validated employing Fischers randomization, test set method and the decoy test method. The validated pharmacophore was allowed to screen the colossal natural compounds database (UNPD). Subsequently, the identified 33 compounds were docked into the proteins active site along with the reference after subjecting them to ADMET and Lipinskis Rule of Five (RoF) employing the CDOCKER implemented on the Discovery Studio. The compounds that have displayed higher dock scores than the reference compound were scrutinized for interactions with the key residues and were escalated to MD simulations. Additionally, molecular dynamics simulations performed by GROMACS have rendered stable root mean square deviation values, radius of gyration and potential energy values. Eventually, based upon the molecular dock score, interactions between the ligands and the active site residues and the stable MD results, the number of Hits was culled to two identifying Hit1 and Hit2 has potential leads against HER2 breast cancers.

Prokaryotic Diversity from Extreme Environments of Pakistan and its Potential Applications at Regional Levels

Extremophiles, the microorganisms thriving in extreme environments, provide valuable resources for practicing novel biotechnological processes. Pakistan homes a wide spectrum of extreme environments which harbor various biotechnologically significant microorganisms. This review gauges the structural and functional bacterial diversity of several extreme environments, emphasizing their potentials as a source of extremozymes, and in bioleaching, bioremediation, and bioenergy production at regional level. Further, this review highlights a panoramic account of the local natural conservatories of extremophiles. The inadequacies of current fragmental research are discussed with suggestions to quantitatively define the structural and functional diversity of unexplored extreme localities.

Molecular and in silico analyses validates pathogenicity of homozygous mutations in the NPR2 gene underlying variable phenotypes of Acromesomelic dysplasia, type Maroteaux

Homozygous and/or heterozygous loss of function mutations in the natriuretic peptide receptor B (NPR2) have been reported in causing acromesomelic dysplasia, type Maroteaux with variable clinical features and idiopathic short stature with nonspecific skeletal deformities. On the other hand, gain of function mutations in the same gene result in overgrowth disorder suggesting that NPR2 and its ligand, natriuretic peptide precursor C (CNP), are the key players of endochondral bone growth. However, the precise mechanism behind phenotypic variability of the NPR2 mutations is not fully understood so far. In the present study, three consanguineous families of Pakistani origin (A, B, C) with variable phenotypes of acromesomelic dysplasia, type Maroteaux were evaluated at clinical and molecular levels. Linkage analysis followed by Sanger sequencing of the NPR2 gene revealed three homozygous mutations including p.(Leu314u2009Arg), p.(Arg371*), and p.(Arg1032*) in family A, B and C, respectively. In silico structural and functional analyses substantiated that a novel missense mutation [p.(Leu314u2009Arg)] in family A allosterically affects binding of NPR2 homodimer to its ligand (CNP) which ultimately results in defective guanylate cyclase activity. A nonsense mutation [p.(Arg371*)] in family B entirely removed the transmembrane domain, protein kinase domain and guanylate cyclase domains of the NPR2 resulting in abolishing its guanylate cyclase activity. Another novel mutation [p.(Arg1032*)], found in family C, deteriorated the guanylate cyclase domain of the protein and probably plundered its guanylate cyclase activity. These results suggest that guanylate cyclase activity is the most critical function of the NPR2 and phenotypic severity of the NPR2 mutations is proportional to the reduction in its guanylate cyclase activity.

Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus

Microglia play a crucial role in the inflammatory brain response to infection. However, overactivation of microglia is neurotoxic. Toll-like receptor 4 (TLR4) is involved in microglial activation via lipopolysaccharide (LPS), which triggers a variety of cytotoxic pro-inflammatory markers that produce deleterious effects on neuronal cells. Ferulic acid (FA) is a phenolic compound that exerts antioxidant and anti-inflammatory effects in neurodegenerative disease. However, the manner in which FA inhibits neuroinflammation-induced neurodegeneration is poorly understood. Therefore, we investigated the anti-inflammatory effects of FA against LPS-induced neuroinflammation in the mouse brain. First, we provide evidence that FA interferes with TLR4 interaction sites, which are required for the activation of microglia-induced neuroinflammation, and further examined the potential mechanism of its neuroprotective effects in the mouse hippocampus using molecular docking simulation and immunoblot analysis. Our results indicated that FA treatment inhibited glial cell activation, p-JNK, p-NFKB, and downstream signaling molecules, such as iNOS, COX-2, TNF-α, and IL-1β, in the mouse hippocampus and BV2 microglial cells. FA treatment strongly inhibited mitochondrial apoptotic signaling molecules, such as Bax, cytochrome C, caspase-3, and PARP-1, and reversed deregulated synaptic proteins, including PSD-95, synaptophysin, SNAP-25, and SNAP-23, and synaptic dysfunction in LPS-treated mice. These findings demonstrated that FA treatment interfered with the TLR4/MD2 complex binding site, which is crucial for evoking neuroinflammation via microglia activation and inhibited NFKB likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.

Ginger ( Zingiber officinale ) phytochemicals—gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches

BackgroundAntibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported.MethodsComputational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis.ResultsBased on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100xa0ns employing GROMACS package.ConclusionsFinally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.