چھتری زمیندار
وسط اپریل گذشتہ میں بمقام بردوان ایک چھتری زمیندار نے ۶ بجے شام کو وفات پائی، متوفی کا تعلق چونکہ سورج بنسی خاندان سے تھا، اس لئے نعش شب میں نہیں جلائی جاسکتی تھی، دوسرے روز صبح سویرے متوفی کے ایک عزیز نے نعش کا فوٹو لیا، لیکن جب فوٹو تیار ہوا تو اس میں پانچ شکلیں اور بھی نظر آئیں، جن میں سے ایک شکل مرحوم کی زوجہ متوفیہ اور ایک مرحوم کے بچہ کی پہچانی گئی، جس کا مدت ہوئے انتقال ہوچکا ہے، باقی تین شکلیں بہت دھندلی آئی ہیں، ان کی شناخت نہ ہوسکی، بنگال کے اخبارات اس روایت کے ذمہ دار ہیں، اور بنگال کے سائنٹفک حلقوں میں اس خبر نے ایک خاص تحریک پیدا کردی ہے۔ (مئی ۱۹۲۰ء)
The novel Corona Virus (nCoV-2019), clouded the entire world during the year 2020; with its emergence in December 2019 from Wuhan, China. The nCoV-19 is a novel variant of the Coronavirus family, with its predecessors been implicated for the pandemics of Middle East Respiratory Syndrome (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV); that caused flu-like condition and respiratory distress symptoms [1-6]. The viral strain also intrudes on extra-pulmonary relevance; being involved with deranging immunity as evidenced by lymphopenia and a prolonged prothrombin time; it impacts cardiomyocytes and pancreatic tissue directly [7-11]. These implications of nCoV-19 does suggest a long-term relevance of the disease profile. The emergenceof nCoV-2019 was quick to gain a pandemic status worldwide. An immense shift in the influx of the type of patients was observed, that imparted a false impression of a reduction in cardiovascular and metabolic patient presentation; formerly that had been the majority engaging the worlds’ healthcare facility. But as the world prepares itself for a possible second wave of the n-CoV-19, a prudent approach would be to remind us of the history lessons from the previous corona-led pandemic, such as MERS and SARS. This editorial will emphasize on channeling our focus to nCoV-19 implications on cardiovascular and metabolic disorders. The pandemics of SARS-CoV during 2002-2003 and MERS-CoV in 2012 highlight the long term relevance of coronavirus to cardiac and metabolic disease pathologies, both during and in the aftermath of these pandemics [3]. The SARS-CoV had demonstrated an increase of cardiovascular problems by 44%, hyperlipidemia by 68% and diabetes mellitus by 60%, in people who had recovered from the viral attack [12, 13]. Likewise, MERS-CoV had also embarked an increase of cardiac disorders by 30% and hypertension by 50% and diabetes mellitus by 50% [3, 8, 9]. Published research on nCoV-19 has hinted for a similar rising trend of cardiovascular and metabolic complexities. An increase in cardiac troponin level is observed with increased cases of myocarditis and heart failure [14]. A 20% increase in the incidence of diabetes and a 40 % rise in cardiovascular and cerebrovascular diseases is observed with nCoV-19 [8, 9]. Little do we comprehend that the involvement of angiotensin converting enzyme 2 (ACE2) receptors could play havoc on endothelium, kidney, intestine, liver and any other organ [15]. The nCoV-19 has thrown a curveball to the realm of the worldwide health and financial setting. Even with the current economic predicament it does seems prudent to be prepared in advance for the long term consequences of this pandemic. The bigger question would be to, not just direct our efforts at countering the possible second wave of nCoV-19 but also for the possible chaos of cardiovascular and metabolic disease outfall, impacting the world health system.
Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Akt isoforms emerged as anti-cancer drug targets because of their constitutive hyperactivation in various oncological disorders. However, due to high intra-family similarity within ATP binding region, the development of isoform-selective modulators of Akt represent a challenging endeavor and thus, until now only a handful of compounds were selected for the clinical investigation. Yet none of them could reach the market for routine clinical use due to their off-target toxicity and poor pharmacokinetic properties. Recent reports on achieving isoform selectivity by designing inhibitors against less conserved pleckstrin homology (PH) domain offer the opportunity to reduce the major off-target toxic effects of Akt antagonists. Therefore, in this thesis, combined ligand- and structure-based in silico strategies have been utilized to probe the key structural features for the inhibition of the PH domain of Akt2 which is more commonly overexpressed in solid tumors. Toward this end, various predictive 2DQSAR (two-dimensional quantitative structure-activity relationship) and GridIndependent Molecular Descriptor (GRIND) and pharmacophore models using structurally diverse data set of 111 quinoline analogs have been developed. Our key findings demonstrate that the presence of three hydrogen bond donors (D1-D3) at a molecular distance of ~8.4, 21.6, 16.8 Å between D1–D2, D1–D3 and D2–D3, respectively is important for selective inhibition of PH domain of Akt2. In addition, our docking results indicated a crucial role of Lys30 for the optimal fit of quinoline-type inhibitors within the binding cavity of the Akt2 PH domain. Moreover, the structurebased pharmacophore model exhibited three hydrogen bond acceptors (A1-A3) at a distance of 4.05 Å (A1-A2), 11.58 Å (A2-A3) and 15.33 Å (A1-A3) that are complementary to the molecular distances identified by GRIND which further validate the reliability of our developed models. Additionally, identified hits through pharmacophoric-based virtual screening provided a new arsenal of potentially selective chemical scaffolds which have a broad structural diversity and less chemical similarity to any of the other known Akt2-PH domain inhibitors. Subsequently, selectivity profiling with the help of proteochemometric modeling revealed essential substructures such as Nmethylpent-3-en-2-amine for selective inhibition of Akt1, methylene amine, isoproenylterazol and 2H-tetrazole for Akt2, and formaldehyde hydrazine for the Akt3 selective inhibition. The present work also illustrates the substructure based similarity search of ChemBridge database to identify Akt2-selective hit compounds. In the present study, one of the selected carboxamide-type hit showed 1.2 and 2.1 fold selectivity against Akt2 as compared to Akt1 and Akt3, respectively. Overall, the work described in this thesis could pave the way towards the identification of potential modulators of Akt2 against cell proliferation in cancer with high isoform-selectivity and limited side effects.