Mechanisms underlying biology at a molecular level are explored through identifying and/or mapping the interactions of proteins with other proteins, nucleic acids, ligands. The methods/tools used are computational and combine representations at various levels, from the coarse-grained to the fully atomistic. The work builds upon foundations that are rooted in rigorous computational biochemistry benchmarked extensively against available experimental data. Simulations complement extensive collaborations with experimental laboratories to provide incisive insights into biology at an atomic level. The group’s current research focuses on several bimolecular mechanisms including those associated with the p53 pathway, kinases, translation initiation, antimicrobials and basic computational biophysical chemistry.
The toolbox used consists of: construction of models based on "imagination with a whiff of hand-waving", homology modelling, molecular dynamics, energy landscapes, reaction paths, ligand-protein/protein-protein dockings including virtual screening, molecular design, machine learning/AI. The group couples the molecular underpinnings of biomolecular regulation with ligand/drug discovery and protein/peptide design both from a therapeutic as well as a (bio)technological perspective.
An extensive program with the p53 laboratory of Prof Sir David Lane combining computer modeling, biophysics, crystallography, molecular/cell biology, investigating the relationship between structural-functional aspects of the p53 family (JMCB 2019) has revealed interesting nuances about the p53 pathway. These have guided us in designing a set of novel constrained (stapled/stitched) peptides whose ability to enter cells and specifically target the p53-MDM2 axis with nanomolar affinities, thus activating p53, has opened a new avenue for designing therapeutics (highlighted in Nature Med 2013 19:120). A major effort has been ongoing with MSD focused on understanding the mechanism of cellular permeabilization and nuclear entry of these peptides and subsequently in using these peptides as probes, therapeutics or vehicles for delivering cargo into cells (Chem Comm 2019; Chem Sci. 2019 10:6457; Molecules 2019). This is being extended to developing constrained/peptides against eIF4E to inhibit translation initiation for a range of cancers (Chem Sci 2019 1:2489). A novel d-amino acid containing stitched peptide has been designed and validated to activate p53, and has recently been patented jointly with MSD. The technology is being expanded to explore a variety of protein-protein interactions in cells for indications ranging from oncology to inflammation (Sci Rep. 2019 9:4913). This collaboration has brought in partners from local organizations, the Universities of Edinburgh, Cambridge, Dundee, Southampton, Newcastle and Harvard and with the pharma Ipsen and MSD.
The recent developments and the excitement generated in the p53 field have been outlined in articles in Nature Reviews Drug Discovery, Nature Reviews in Cancer, Nature Reviews in Clinical Oncology that has been published by the joint efforts of teams from Singapore, Karolinska,Cambridge & Harvard Universities. The program is supported by generous funding from A*STAR and MSD.
A highly successful interdisciplinary program with the group of Prof Beuerman at the Singapore Eye Research Institute and researchers at National University of Singapore, Singapore General Hospital, Duke-NUS and Tan Tok Sing Hospital has resulted in the design of novel antimicrobials. These molecules target membranes with rapid killing times, are non-toxic to human cells and appear to avert resistance in bacteria. The greater anionicity of the bacterial membranes appears to be responsible for the rapid adsorption and hence killing of the former and for the non-toxicity of these cationic molecules; the inability of bacteria to easily remodel their membranes possibly leads to their susceptibility (J Phys Chem B 2018 122 8698). The molecules work against a range of gram-positive and gram-negative organisms including resistant MRSA. A unique platform outlining the first reported in-membrane fragment based design method has been developed and several patents filed. A spinoff company has been set up (www.sinsalabs.com). Recently we have developed a novel molecule that is able to disrupt the new mcr-1 resistant bacterial membrane (which is resistant to colistin) and enables colistin to be active at low doses. A patent has been filed and discussions for a new spinoff are in progress.
The Kinase Pathways
In a large translational effort, the group is engaged with experimentalists (Dr Scaltriti, MSKCC), Dr Uttam Surana (IMCB) and clinicians Dr Daniel Tan (GIS, SGH, NCC Singapore), Dr Goh Boon Cher (NUHS) studying the effects of small molecule and antibody based therapies for cancers (Cancer Cell 2016). This work is now directed at the putative effects of mutations and SNPs (JCIM 2019a,c) in patients on drugs used in the clinic.
The translational and clinical focus of the group is backed by rigorous investigations into fundamental questions regarding the modulation of biomolecular function, developments of analytical processes, relationships between flexibility, thermodynamics, kinetics and function in biomolecules, role of water molecules and development of methods to enable discovery (Nat Commun 2019; NAR 2019; JICM 2019a,b,c,d; DDT 2019; NAR 2019 47(W1):W482)
The virtual screening and peptide design efforts of the group are extended to collaborations with various groups within A*STAR (including the Experimental Drug Discovery Centre, IMCB, IMB, SIGN, p53Lab, MEL, SBIC, ICES), the hospitals in Singapore, research centres (National Cancer Centre, Cancer Science Institute, LKC), universities (NUS, NTU, Duke-NUS) and organizations elsewhere (Univ of Cambridge, Karolinska Instt, MSKCC, Pasteur Institute), who carry out the synthesis and experimental investigations of the compounds. Programs that combine the strengths of various institutes, hospitals and universities in Singapore towards peptide engineering (Molecules 2019), wound healing, precision medicine (Cell 2019), bioimaging and small molecule discovery are generously funded by the Industry Alignment Fund Pre-Positioning grant. Combining a new yeast-based platform and modelling with colleagues in A*STAR at IMCB and BTI has resulted in several new molecules against targets in oncology. A novel potential therapeutic for wet-AMD which is being pursued in our spinoff Sinopsee Therapeutics has shown exciting results in mice and is currently at the stage of seeking Series A funds. The computational expertise of the group is now being amalgamated in a new spinoff Aplomex which will be focused on designing peptides, proteins and antibodies.
The success of the group in interfacing the nanoscale with experimental observations has encouraged several experimental groups worldwide to participate with us. These have also resulted in joint graduate programs with various universities including Southampton, Manchester, Essex.
Chandra Verma joined the Bioinformatics Institute (BII) A*STAR, Singapore, in November 2003. He heads the division of Biomolecular Modelling and Design and leads a group that applies physics based models to understand the links between protein sequence, structure and biological function. His group works closely with experimental laboratories where the hypotheses generated are tested. In addition, the group is also involved in designing peptides and small molecules (through virtual screening) both for interrogating biology as well as for therapeutic purposes. Prior to joining Singapore, he worked at the Structural Biology Laboratory in York, UK. He obtained his undergraduate degree at the Indian Institute of Technology, India and his D. Phil at the University of York