Biology subjects

Othman, H.

Publications and source records attributed to Othman, H..

5 recordsLinked to original sources

bioRxiv2021

SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the Receptor Binding Domain: evidence from structural analysis and microscale accelerated molecular dynamics

The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. The hypothesis was supported by sequence and structural analysis. However, given that the microenvironment of the RGD motif imposes structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, by molecular dynamics, that neither RGD motif nore its microenvironment show any significant conformational shift in the RBD structure. Highly populated clusters were used to run a protein-protein docking against three RGD-binding integrin types, showing no capability of the RBD domain to interact with the RGD binding site. Moreover, the free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. Our results highlighted different structural features of the RGD motif that may prevent its involvement in the interaction with integrins. We, therefore, suggest, in the case where integrins are confirmed to be the direct host receptors for SARS-CoV-2, a possible involvement of other residues to stabilize the interaction.

bioinformatics↗

bioRxiv2021

Single nucleotide polymorphism induces divergent dynamic patterns in CYP3A5: a microsecond scale biomolecular simulation of variants identified in Sub-Saharan African populations

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigates the impact of such variants on protein structure to assess their functional importance. We use genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype, and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability acts on the plasticity of the protein. The impact on drug binding may be drug dependant. We conclude that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

bioinformatics↗

bioRxiv2020

The extent and impact of variation in ADME genes in sub-Saharan African populations

Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterising pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterised in European and Asian populations, but African populations are under-studied - which has implications for safe and effective drug use in Africa. The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterisation of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations. Author summaryThe ADME genes are a group of genes that play a key role in absorption, distribution, metabolism and excretion of drugs. Variations in these genes can have a significant impact on drug safety and efficacy. Africa has a high level of genetic variation and is under-studied in drug development, which makes study of variations in these genes in African populations very important. Using a new data set of 458 high-coverage genomes from across Africa, we characterise the extent and impact of variation in the ADME genes, looking at both single nucleotide and copy number variations. We identified 343,368 variants, including 40,692 novel variants, and 930 coding variants which are predicted to have high impact on function. Our discovery curves indicate that there will be considerable value in sequencing more African genomes. Moreover, relatively few of these novel variants are captured on common genotyping arrays. We show that there is considerable diversity within Africa in some important genes, and this will have significant consequences for the emerging field of precision medicine in Africa.

genetics↗

bioRxiv2020

In silico study of the spike protein from SARS-CoV-2 interaction with ACE2: similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism

The spread of COVID-19 caused by the SARS-CoV-2 outbreak has been growing since its first identification in December 2019. The publishing of the first SARS-CoV-2 genome made a valuable source of data to study the details about its phylogeny, evolution, and interaction with the host. Protein-protein binding assays have confirmed that Angiotensin-converting enzyme 2 (ACE2) is more likely to be the cell receptor through which the virus invades the host cell. In the present work, we provide an insight into the interaction of the viral spike Receptor Binding Domain (RBD) from different coronavirus isolates with host ACE2 protein. By calculating the binding energy score between RBD and ACE2, we highlighted the putative jump in the affinity from a progenitor form of SARS-CoV-2 to the current virus responsible for COVID-19 outbreak. Our result was consistent with previously reported phylogenetic analysis and corroborates the opinion that the interface segment of the spike protein RBD might be acquired by SARS-CoV-2 via a complex evolutionary process rather than a progressive accumulation of mutations. We also highlighted the relevance of Q493 and P499 amino acid residues of SARS-CoV-2 RBD for binding to human ACE2 and maintaining the stability of the interface. Moreover, we show from the structural analysis that it is unlikely for the interface residues to be the result of genetic engineering. Finally, we studied the impact of eight different variants located at the interaction surface of ACE2, on the complex formation with SARS-CoV-2 RBD. We found that none of them is likely to disrupt the interaction with the viral RBD of SARS-CoV-2.

bioinformatics↗

bioRxiv2020

Small-scale field assessment of efficacy of the autodissemination approach against Aedes sp. in an urban area.

This is the first study to evaluate the efficacy of an autodissemination approach, as suggested by WHO. Therefore, the efficacy of an autodissemination approach in small-scale field trials against wild Aedes sp. population was evaluated in an urbanized setting, Malaysia. Lethal ovitraps enhanced with pyriproxyfen were used to control Aedes sp. populations at treatment sites, with the autodissemination activity was assessed using the WHO larval bioassays. Lethal ovitraps enhanced with pyriproxyfen effectively reduced of Aedes sp. population. All autodissemination stations were shown to be visited by Aedes sp. mosquitoes with 100% complete inhibition against eggs and larvae development. In the larvae bioassay, pupae mortality ranged from 14 to 40%. Statistically, a significant reduction of Aedes sp. population in the treatment sites compared to the untreated areas. The study proved for the autodissemination of pyriproxyfen to breeding habitats by wild Aedes sp. This technique is highly potentially for vector control activities. Future evaluation should focus on large-scale field trials. Author SummarySince 2012, Dataran Automobil, Seksyen 15, Shah Alam, was declared as one of the dengue hotspot areas. Major vector control activities were conducted by government, NGOs, social communities, and local authorities, but the number still rising. We conducted a new invention of autodissemination concepts in this area by an entomological study on mosquito populations reduction and dispersal abilities of the technique. We found that the technique has proven to control mosquito populations, but the other factors such as epidemiology link still unclear and need further clarification. Our finding highlighted the effectiveness of autodissemination strategies that can be considered as one of the alternative tools in vector control programme.

ecology↗