Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single-stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S-protein priming by host cell serine protease TMPRSS2. Recently, COVID19 has been declared pandemic by World Health Organization (WHO) yet high differences in disease outcomes across countries have been seen. We provide evidences to explain these population-level differences. One of the key factors of entry of the virus in host cells presumably is because of differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that a higher expression of ACE2 is facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs), with different frequencies in different populations. We suggest that high expression of ACE2 results in homo-dimerization, proving disadvantageous for TMPRSS2 mediated cleavage of ACE2; whereas, the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs in TMPRSS2 and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of the Virus in host cells. In addition, we suggest that several key host genes, like SLC6A19, ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3 and some other proteases as Cathepsins, might have a critical role. To conclude, understanding population specific differences in these genes may help in developing appropriate management strategies for COVID19 with better therapeutic interventions.

Acute drug resistance, intolerable side effects and non-specific target activation are the crucial barriers for efficient translational outcome of target directed cancer drug discovery. In the last five years, many of the bull’s eye drugs failed to obtain FDA approval because of highly complicated mechanisms of the targeting receptors. These receptors include epidermal growth factor receptor (EGFR) and Insulin-like growth factor receptor 1 (IGF 1R), and are considered as pivotal signaling routes in highly transformed metastatic cancers. IGF 1R and EGFR families show homology in their structure and both the receptors share considerable crosstalk in their functions. An aberrant activation of these two pathways is often diagnosed among many cancer patients. Therefore, target based monoclonal antibodies and small molecule tyrosine kinase inhibitors, either in combination or co-targeting these two receptors may provide a new era of promising therapy and can help in remarkable progress among cancer patients.

The prevailing multi-drug resistance in Mycobacterium tuberculosis continues to remain one of the main challenges to combat tuberculosis. Hence, it becomes imperative to focus on novel drug targets. Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein, a eukaryotic tubulin homologue and a promising drug target. During cytokinesis, FtsZ polymerises in the presence of GTP to form Z-ring and recruits other proteins at this site that eventually lead to the formation of daughter cells. Benzimidazoles were experimentally shown to inhibit Mtb-FtsZ, with one of the benzimidazole derivatives, M1, being reported to have the minimum inhibitory concentration (MIC) value of 3.13µg/ml. In the present study, mechanism of destabilization of FtsZ in the presence of M1 was computationally investigated in the presence of its substrate GTP/GDP employing Molecular dynamics (MD) simulation analysis, principal component analysis (PCA), molecular mechanics combined with the generalized Born and surface area continuum salvation (MM-GBSA), and density functional theory (DFT). From the analyses it is proposed that binding of M1 in the inter-domain cleft induces structural changes in the GTP binding region that affect GTP binding, thus switching the preference of this protein towards depolymerised state and eventually inhibiting the cell division. Hence, this study provides mechanistic insights into the design of novel benzimidazole inhibitors against Mtb-FtsZ.

Epidermal growth factor receptor kinase is implicated in cancer development due to either overexpression or activation variants in its functional intracellular kinase domain. Threonine to methionine (Thr 790 Met) is one such variant observed commonly in patients showing resistance to kinase inhibitor drug Erlotinib. Two mechanisms for resistance have been proposed (1) steric hindrance and (2) enhanced binding to ATP. In this study, we employed molecular dynamics simulations and studied both the mechanisms. Extensive simulations and free energy of binding analyses has shown that steric hindrance does not explain appropriately the mechanism for resistance against Erlotinib therapy for this variant. It has been observed that conformational switching from an intermediate intrinsically disordered C-helix conformation is required for completion of the kinase’s catalytic cycle. Our study substantiates that T790M variant has greater tendency for early transition to this intrinsically disordered C-helix intermediate state. We propose that enhanced catalytic efficiency in addition to enhanced ATP binding explains mechanism of T790M resistance to drug Erlotinib.