It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the so-called incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the single-target drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery.

Enzymes play a powerful role as catalysts with high specificity and activity under mild environmental conditions. Significant hurdles, such as reduced solubility, reduced shelf‐life, aggregate formation, and toxicity, are still ongoing struggles that scientists come across when purifying recombinant proteins. Over the past three decades, PEGylation techniques have been utilized to significantly overcome low solubility; increased protein stability, shelf‐life, and bioactivity; and prevented protein aggregate formation. This review seeks to highlight the impact of PEG‐based formulations that are significantly utilized to obtain favourable protein physiochemical properties. The authors further discuss other techniques that can be employed such as coexpression studies and nanotechnology‐based skills to obtaining favourable protein physiochemical properties.

The SARS-CoV-2 spike protein is pivotal in the COVID-19 virus’s life cycle, facilitating viral attachment to host cells. It is believed that targeting this viral protein could be key to developing effective COVID-19 prophylactics. Using in silico techniques, this study sought to virtually screen for compounds from the literature that strongly bind and disrupt the stability of the HSPA8–spike protein complex. To evaluate the interactions between the individual proteins and the protein complex attained from protein–protein docking using BioLuminate, molecular docking was performed using the Maestro Schrodinger Suite. The screened small molecules met all bioavailability conditions, Lipinski’s and Veber’s rules, and the required medicinal chemistry properties. Protein–protein docking of the spike protein and HSPA8 identified the optimal pose with a PIPER cluster size of 65, a PIPER pose energy of −748.301 kcal/mol, and a PIPER pose score of −101.189 kcal/mol. Two small molecules, NSC36398 and NSC281245, showed promising docking scores against the spike protein individually and in a complex with HSPA8. NSC36398 had a docking score of −7.934 kcal/mol and a binding free energy of −39.52 kcal/mol with the viral spike protein and a docking score of −8.029 kcal/mol and binding free energy of −38.61 with the viral protein in complex with HSPA8, respectively. Mevastatin had a docking score of −5.099 kcal/mol and a binding free energy of −44.49 kcal/mol with the viral protein and a docking score of −5.285 kcal/mol and binding free energy of −36.65 kcal/mol with the viral protein in complex with HSPA8, respectively. These results, supported by extensive 2D interaction diagrams, suggest that NSC36398 and NSC281245 are potential drug candidates targeting SARS-CoV-2 spike protein.

The exposure of organisms and cells to unfavorable conditions such as increased temperature, antibiotics, reactive oxygen species, and viruses could lead to protein misfolding and cell death. The increased production of proteins such as heat shock proteins (HSPs) and polyamines has been linked to protein misfolding sequestration, thus maintaining, enhancing, and regulating the cellular system. For example, heat shock protein 40 (Hsp40) works hand in hand with Hsp70 and Hsp90 to successfully assist the newly synthesized proteins in folding properly. On the other hand, polyamines such as putrescine, spermidine, and spermine have been widely studied and reported to keep cells viable under harsh conditions, which are also involved in cell proliferation, differentiation, and growth. Polyamines are found in all living organisms, including humans and viruses. Some organisms have developed a mechanism to hijack mammalian host cell machinery for their benefit like viruses need polyamines for infection. Therefore, the role of HSPs and polyamines in SARS-CoV-2 (COVID-19) viral infection, how these molecules could delay the effectiveness of the current treatment in the market, and how COVID-19 relies on the host molecules for its successful infection are reviewed.

Heat shock proteins are molecular chaperones that play crucial roles in the folding and unfolding of complex polypeptides within the cellular system. These molecules are involved in various processes, including vesicular transport, prevention of protein aggregation in the cytosol, and cell signaling. They are also linked to autoimmunity, infection immunity, and tumor immunology. Stressors like heat shock, exposure to heavy metals, cytokines, reactive oxygen species, inflammation, and viruses can influence the production of these molecules. In complex diseases such as cancer, malaria, and COVID-19, heat shock proteins are considered both biomarkers and drug targets. The upregulation of small heat shock proteins like hsp27 and major heat shock proteins 70/90 has been recognized as crucial biomarkers and therapeutic targets for cancer. Additionally, it has been reported that the invasion of Plasmodium falciparum, the causative agent of malaria, leads to the upregulation of heat shock proteins such as hsp40, hsp70, and hsp90. This sudden increase is a protective mechanism from the human host and enhances the parasite’s growth, making these proteins significant as biomarkers and malarial drug targets. The presence of the SARS-CoV-2 virus in the human cellular system correlates with a substantial increase in heat shock protein 70 production from host cells. Furthermore, our research group has demonstrated that SARS-CoV-2 hijacks the host’s heat shock proteins, and we are currently developing tools to prevent the virus from utilizing the host’s protein folding system. This review aims to highlight the role of heat shock proteins as biomarkers and therapeutic targets for selected refractory diseases, focusing on cancer, malaria, and COVID-19. A fundamental molecular docking study was performed to investigate the interaction between a non-structural complex from SARS-CoV-2 and chosen small molecules, which is emphasized in this review.

Coronavirus disease 2019 (COVID-19) is a novel disease that had devastating effects on human lives and the country’s economies worldwide. This disease shows similar parasitic traits, requiring the host’s biomolecules for its survival and propagation. Spike glycoproteins severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 spike protein) located on the surface of the COVID-19 virus serve as a potential hotspot for antiviral drug development based on their structure. COVID-19 virus calls into action the chaperonin system that assists the attacker, hence favoring infection. To investigate the interaction that occurs between SARS-CoV-2 spike protein and human molecular chaperons (HSPA8 and sHSP27), a series of steps were carried out which included sequence attainment and analysis, followed by multiple sequence alignment, homology modeling, and protein–protein docking which we performed using Cluspro to predict the interactions between SARS-CoV-2 spike protein and human molecular chaperones of interest. Our findings depicted that SARS-CoV-2 spike protein consists of three distinct chains, chains A, B, and C, which interact forming hydrogen bonds, hydrophobic interactions, and electrostatic interactions with both human HSPA8 and HSP27 with −828.3 and −827.9 kcal/mol as binding energies for human HSPA8 and −1166.7 and −1165.9 kcal/mol for HSP27.